A Diastereodivergent and Enantioselective Approach to syn- and anti-Diamines: Development of 2-Azatrienes for Cu-Catalyzed Reductive Couplings with Imines that Furnish Allylic Amines

Abstract

We introduce a new reagent class, 2-azatrienes, as a platform for catalytic enantioselective synthesis of allylic amines. Herein, we demonstrate their promise by diasteredivergent and enantioselective synthesis of <i>syn</i>- and <i>anti</i>-1,2-diamines by Cu-bis(phosphine)-catalyzed reductive couplings with imines. With Ph-BPE, <i>anti</i>-diamines are obtained, and with the rarely utilized t-Bu-BDPP, <i>syn</i>-diamines are generated.<br />

Copper-Catalyzed Diastereo-, Enantio-, and (Z)-Selective Aminoallylation of Ketones through Reductive Couplings of Azatrienes for the Synthesis of Allylic 1,2-Amino Tertiary Alcohols

“…Electronrich ketones often lead to high diastereoselectivity as well but lower enantioselectivity (16:1 dr, 88.5:11.5 er for 3b) whereas more electron-poor ketones lead to lowering of both stereoselectivity metrics (compare 3d−g). Although the trends seem clear that diastereo-and enantioselectivity both decrease as the ketones become more electron-rich or electron-poor from acetophenone, compared to our (E)-selective azatriene reductive couplings with aldimines, 16 where enantioselectivity was uniformly high but diastereoselectivity modulated similarly with respect to electrophile electronics, the linear free energy correlations with these ketone data are moderate. 20 Reaction of m-methyl acetophenone furnishes tertiary alcohol 3h with 14:1 dr and 96:4 er, and a naphthyl ketone affords 3j in 11:1 dr and 90.5:9.5 er.…”

“…We first explored the feasibility of ketone aminoallylation by reductive coupling of azatriene 1 with acetophenone under conditions similar to our previously reported azatriene−imine couplings that afford anti-1,2-diamines bearing an (E)-alkene (Table 1, entry 1). 16 Compared to those reactions with Cu(Ph-BPE) as the catalyst, in THF, the ketone addition furnishes imino silyl ether 2a with >98% (Z)-selectivity as a 13:1 mixture of diastereomers favoring the anti-isomer. For ease of handling and isolation, the imine and ether of 2a were hydrolyzed to the corresponding hydroxy ammonium salt, which was converted to its benzamide derivative to afford 3a (70% isolated yield, 99:1 er).…”

“…15 Inspired by that disclosure, we have developed a (Z)-selective aminoallylation of ketones through reductive coupling of 2-azatrienes, a new class of enamine umpols reported by our laboratory. 16 Reactions are highly stereoselective and take place with both aryl/alkyl and dialkyl ketones, significantly expanding the chemical space available within enantioenriched 1,2-amino tertiary alcohols that may be readily accessed through C−C bond formation. 12,17 alizations of the products, including those that take advantage of the amino alcohol's nearby (Z)-alkene, highlight the synthetic utility of this method.…”

Diastereodivergent Catalysis

“…As a new platform for Cu I / bisphosphine-catalyzed reductive couplings with imines, the Malcolmson group introduced a new Umpolung reagent, 2azatriene, to synthesize allylic amines (Scheme 6). 45 Utilizing L6 as the ligand in combination with Cu(OAc) 2 , enantioenriched anti-diamines were obtained with exquisite diastereocontrol. Under otherwise identical conditions, the ligand L7 promotes the formation of syn-diamines with 94% ee and >20:1 d.r.…”

Chemoselective Diazine Dearomatization: The Catalytic Enantioselective Dearomatization of Pyrazine

“…26−34 A breakthrough in the preparation of C 1 -symmetric 1,2-diamines has yet to be made with the current state-of-the-art reliant on amino acid and chiral auxiliary approaches. 21 Although beautiful catalytic processes toward 1,2-diamines have been reported by the Malcolmson group, 35,36 more general and complementary approaches have yet to appear.…”