Asymmetric Retro-Claisen Reaction by Synergistic Chiral Primary Amine/Palladium Catalysis

Abstract

We described herein a chiral primary amine/palladium catalyzed asymmetric retro-Claisen reaction of β-diketones with salicylic carbonates. A series of chiral α-alkylated ketones and macrolides were obtained with good yields and excellent enantioselectivities upon a sequence of decarboxylative benzylation, retro-Claisen cleavage, and enamine protonation. This strategy features broad substrate scope, mild conditions, as well as high atom economy with salicylic carbonates as the o-quinone methide precursors.

Iridium-Catalyzed Asymmetric Cascade Allylation/Retro-Claisen Reaction

“…The asymmetric catalytic cascade reaction generally emerged as a valuable and powerful tool to construct complex chiral molecules with functional diversity, which always features high synthetic efficiency, excellent selective control, and greatly subtractive operation numbers/steps. − Therefore, it could potentially work as an efficient protocol to resolve these challenging problems. Vinylethylene carbonate (VEC) has been intensively employed as an important precursor for the generation of dipoles in cycloaddition reactions, , which also could work as important reaction partners to introduce homoallylic alcohol manifolds. − Driven by the widespread occurrence of the key 3-hydroxymethyl pentenal skeletons, as illustrated in Scheme b, we designed a conceptually new cascade synthetic strategy based on the combination of our recent studies on Ir-catalyzed enantioselective allylation of readily available VEC , and the subsequent intramolecular retro-Claisen reaction. − The protocol has its good points of simplicity, convergence, and high atom economy with carbon dioxide as the sole byproduct. According to the retrosynthetic analysis, the initial Ir-catalyzed asymmetric allylation − of β-diketones with VEC could lead to the crucial intermediate 2,4-dione bearing hydroxymethyl group I in an enantiopure form, which then undergoes a retro-Claisen reaction, leading to the expected key functionalized chiral 3-hydroxymethyl pentenal units.…”

Highly Stereoselective Construction of β,β-Diaryl-α-Branched Ketones by the Chiral Primary Amine-Catalyzed Asymmetric Retro-Claisen Reaction

“…10 In both processes, the reactions were Herein, we report a highly stereoselective construction of chiral β,β-diaryl-α-branched ketones by the chiral primary amine-catalyzed asymmetric retro-Claisen reaction of βdiketones with o-quinone methides (o-QMs) (Scheme 1b). Recently, we developed a chiral primary amine-catalyzed asymmetric retro-Claisen reaction 18,19 Our study commenced with the primary amine-catalyzed asymmetric retro-Claisen reaction of the β-diketone (1a) with the aryl-substituted o-QM (2a) in the presence of a chiral primary amine catalyst and an acid additive. The reaction afforded the desired product 3aa in 81% yield, >20:1 dr, and 98% ee under the standard conditions (Table 1, entry 1).…”

“…Herein, we report a highly stereoselective construction of chiral β,β-diaryl-α-branched ketones by the chiral primary amine-catalyzed asymmetric retro-Claisen reaction of β-diketones with o -quinone methides ( o -QMs) (Scheme b). Recently, we developed a chiral primary amine-catalyzed asymmetric retro-Claisen reaction , of β-diketones with o -QMs generated in situ . It was found that forming the enamine intermediate could capture the o -QM intermediate and trigger subsequent asymmetric C–C bond cleavage − and stereospecific enamine protonation processes.…”

“…Recently, we developed a chiral primary amine-catalyzed asymmetric retro-Claisen reaction , of β-diketones with o -QMs generated in situ . It was found that forming the enamine intermediate could capture the o -QM intermediate and trigger subsequent asymmetric C–C bond cleavage − and stereospecific enamine protonation processes. The intermediate generated by the o -QM precursor is highly active and unstable and can create only one chiral center because of the unsubstituted methylene.…”

“…The high stereoselectivity of the reaction can be rationalized by considering the proposed transition states illustrated in Scheme . , In these transition states, multiple hydrogen bond interactions between enamine and o -QM provided rigid environments for the tandem reaction to occur successively. Re facial attack of the enamine intermediate from the Si face of o -QM then afforded the observed single stereoisomer.…”