Palladium-Catalyzed Asymmetric Allylic Alkylation/α-Iminol Rearrangement: A Facile Access to 2-Spirocyclic-Indoline Derivatives

Abstract

An unprecedented Pd-catalyzed asymmetric allylic alkylation of 1-(indol-2-yl)cyclobutanols followed by an -iminol rearrangement was reported. High yields with excellent chemo-, regio-, diastereo-, and enantioselectivities have been realized, affording a wide range of enantioenriched 2-spirocyclic-indolines bearing two contiguous stereocenters. The facial-selectivity of the ensuing rearrangement is controlled by the subtle difference of the substituents on the formed all-carbon quaternary stereogenic center in the allylic alkylation step. Non-activated racemic terminal allylic alcohols were utilized as efficient electrophiles via kinetic resolution pathway for the first time in Pd-catalyzed asymmetric allylic alkylation.The roles of Et 3 B additive are pivotal to activating allylic alcohols towards the formation of allylpalladium species and suppressing N/O allylic alkylation of indole with enhanced C3-nucleophilicity. ESI-HRMS experiments provided strong evidence for the existence of the key nucleophilic boron anionic species, which fully accounts for the essential roles of Et 3 B additive. Mechanism study indicates that the real catalytically active species is an electronic -cinnamyl-palladium complex coordinated by two phosphoramidite ligands, which is consistent with the observed non-linear effect and control experiments, and further confirmed by X-ray structure analysis.

Cooperative Catalyst‐Enabled Regio‐ and Stereodivergent Synthesis of α‐Quaternary α‐Amino Acids via Asymmetric Allylic Alkylation of Aldimine Esters with Racemic Allylic Alcohols

“…Considering the dual activation of racemic allylic alcohols and aldimine esters with Et 3 B in Cu/Pd‐catalyzed linear selective asymmetric α‐allylation, we wondered whether this cooperative catalysis system could be further extended to our previously developed Cu/Ir‐catalyzed asymmetric and stereodivergent α‐allylation of aldimine esters [13c] . The key issue is the feasibility of ionization of the hydroxyl group in the racemic allylic alcohol through the activation of Et 3 B to generate the electrophilic Ir‐π‐allyl species [23, 24] amenable to nucleophilic attack of the in situ‐formed Cu I ‐ylide at the more substituted allylic termini. Previously, the Et 3 B reagent was revealed to be an invalid promoter in the Ir‐catalyzed asymmetric amination of linear allylic alcohols [17g] .…”

“…The Cu/Pd-catalyzed α-allylation with Et 2 Zn occurred with low conversion, albeit with improved enantioselectivity (entry 6). To our delight, with Et 3 B as the additive, [23,24] the reaction occurred with exclusive regioselectivity, and 3 a was obtained in 45 % yield and 95 % ee (entry 7). However, experiments conducted with several related Lewis acids, such as AlEt 3 or AlEt 2 Cl, led to complete suppression with no conversion (entries 8 and 9).…”

Zinc-Catalyzed Enantioselective [3 + 3] Annulation for Synthesis of Chiral Spiro[indoline-3,4′-thiopyrano[2,3-b]indole] Derivatives

“…However, there are no reports on metal-catalyzed asymmetric cascade annulations of the indoline-2-thiones. Herein, we describe the application of Bronsted base and Lewis acid cooperative activation [ 44 , 45 , 46 , 47 ] to the synthesis of spiro[indoline-3,4′-thiopyrano[2,3- b ]indole] derivatives via the Friedel–Crafts alkylation/cyclization tandem reactions of indoline-2-thiones and isatylidene malononitriles [ 48 , 49 , 50 , 51 ] ( Scheme 1 b).…”

Pd-Catalyzed intermolecular asymmetric allylic dearomatization of 1-nitro-2-naphthols with MBH adducts

“…Dearomatization reactions can transform planar aromatic compounds into three-dimensional chiral molecules. 1 β-Naphthalenone is a core skeleton widely found in natural products and biologically active molecules. 2 Therefore, extensive efforts have been dedicated to the construction of β-naphthalenones through dearomatization of 2-naphthol derivatives.…”