Traversing Steric Limitations by Cooperative Lewis Base/Palladium Catalysis: An Enantioselective Synthesis of α‐Branched Esters Using 2‐Substituted Allyl Electrophiles

Abstract

Cooperative catalysis enables the direct enantioselective α-allylation of linear prochiral esters with 2-substituted allyl electrophiles. Critical to the successful development of the method was the recognition that metal-centered reactivity and the source of enantiocontrol are independent. This feature is unique to simultaneous catalysis events and permits logical tuning of the supporting ligands without compromising enantioselectivity.

Enantioselective α‐Benzylation of Acyclic Esters Using π‐Extended Electrophiles

“…[8] Proceeding via C1-ammonium enolate nucleophiles, this construct results in a general reaction template that accommodates a variety of transition-metal-catalyzed processes. [9] Herein, we further advance our cooperative framework by demonstrating, for the first time, that C1-ammonium enolates effectively react with putative cationic π-(benzyl)Pd II electrophiles, enabling the highly enantioselective benzylic alkylation of aryl- and alkenylacetic acid esters with π-extended benzylic phosphate electrophiles (Figure 1 d).…”

“…[6] Within our cooperative catalysis framework we have also observed the drastic effect that the nucleofuge plays in enantioselection. [8] Mindful of these observations, we surveyed a range of activated 2-naphthyl alcohol derivatives (Table 1). …”

A Regio‐ and Stereodivergent Synthesis of Homoallylic Amines by a One‐Pot Cooperative‐Catalysis‐Based Allylic Alkylation/Hofmann Rearrangement Strategy

“…Thereafter, we examined the scope of allyl sulfonate electrophiles (Scheme ). Employing Pd[P(2‐thienyl) 3 ] 3 ( B ) as the catalyst enabled 2‐substituted allyl electrophiles to react effectively, giving functionalized homoallylic amines 20 – 22 , the latter containing a trimethylsilylacetylene substituent. Using the same catalyst, ester ( 23 and 24 ), Weinreb amide ( 25 ), and secondary amide ( 26 ) substituted allyl electrophiles were also effective .…”

“…First, all aspects of enantio‐, regio‐, and diastereodivergent C(sp 3 )−C(sp 3 ) formation could be controlled by judicious choice of the Lewis base/transition‐metal catalyst combination (see Figure c, cooperative catalysis). Second, rapid in situ conversion of product Pfp esters (not shown) into intermediate primary amides would permit subsequent stereospecific Hofmann‐type rearrangement to forge the necessary C(sp 3 )−N bond via isocyanates (see Figure c, isocyanate intermediates). These could be intercepted with an appropriate alcohol (R 1 ‐OH) to give the corresponding carbamate‐protected or unprotected enantioenriched linear or branched homoallylic amines.…”

Synergistic N‐Heterocyclic Carbene/Palladium‐Catalyzed Umpolung 1,4‐Addition of Aryl Iodides to Enals

“…, bottom), using Pd 2 -(dba)3 (5 mol %)/BINAP (10 mol %) as the metal catalyst, KO t Bu (to deprotonate the NHC precatalyst shown at the bottom of Table 1) in THF/MeOH (20:1) at room temperature for 12 h(Table 1, entries 1-4). To our delight, the more sterically hindered NHC precursor N1 furnished the 1,4addition product methyl b,b-diphenyl propanoate (3aa)i n 22 %assay yield (AY, determined by 1 HNMR integration of the unpurified reaction mixture against an internal standard; Table 1, entry 1).…”