Pushing the Limits of Aminocatalysis: Enantioselective Transformations of α-Branched β-Ketocarbonyls and Vinyl Ketones by Chiral Primary Amines

Abstract

Enantioselective α-functionalizations of carbonyl compounds are fundamental transformations for the asymmetric synthesis of organic compounds. One of the more recent developments along this line is in aminocatalysis, which leads to the direct α-functionalization of simple aldehydes and ketones. However, most of the advances have been achieved with linear aldehydes and ketones as substrates. Effective aminocatalysis with α-branched carbonyls, particularly α-branched ketones, has remained elusive. The primary difficulty arises from the space-demanding α-substituent, which impedes iminium/enamine formation. In 2005, synthetic organic chemists revived catalysis using primary amines, which brought new attention to these challenges, because of the conformational flexibility of primary amines. On the basis of early biomimetic studies by Hine, in 2007 we developed the bioinspired chiral primary amine catalysts featuring primary-tertiary diamines. This type of catalyst involves enamine/iminium catalysis, and we could apply this chemistry to all of the major types of ketones and aldehydes. In this Account, we present research from our laboratory that significantly expands aminocatalysis to include α-branched ketones such as β-ketocarbonyls and α-substituted vinyl ketones. Our primary amine catalysis methodology, when used alone or in conjunction with metal catalysts, provides convenient access to both enantiopure α-tertiary and quaternary ketones, structures that are not available via other approaches. Our mechanistic studies showed that acidic additives play the critical role in facilitating catalytic turnover, most likely by shuttling protons during the enamine/iminium tautomerizations. These additives are also critical to induce the desired stereochemistry via ammonium N-H hydrogen bonding. Proton transfer by shuttling is also stereoselective, resulting in enantioselective enamine protonation as observed in the reactions of α-substituted vinyl ketones. In addition, we have carried out density functional theory studies that help to delineate the origins of the stereoselectivity in these reactions.

Visible Light Promoted β‐C—H Alkylation of β‐Ketocarbonyls via a β‐Enaminyl Radical Intermediate

“…Methyl acrylate was initially selected as the electrophilic coupling partner. To our delight, we obtained the desired β-alkylation in nearly quantitative yield ( Table 1, entry 1), when employing Ir(ppy) 2 (dtbbpy)PF 6 as photocatalyst and a catalytic amount of quinine as base. Among the photocatalysts screened, only Ir[(dFCF 3 (ppy) 2 )]dtbbpy could promote the coupling reaction efficiently (entries 5 -7).…”

“…Based on our previous works on secondary enamine carbonyls, [6] we have explored 5πe carbonyl activation with preformed secondary enamine carbonyls under photoredox catalysis. [7] The expected transient β-enaminyl radical intermediate, formed via an enamine oxidation/C-H deprotonation sequence, could be intercepted by a Michael acceptor, thus generating the direct β-alkylation products of β-ketocarbonyls .…”

Resonance‐Assisted Hydrogen Bonding as a Driving Force in Synthesis and a Synthon in the Design of Materials

“…[150][151][152] They have been extensively used as key intermediates in organic synthesis [153][154][155] and as ligands in coordination chemistry, [156][157][158] and can be synthons in bioactive natural products. [150][151][152] They have been extensively used as key intermediates in organic synthesis [153][154][155] and as ligands in coordination chemistry, [156][157][158] and can be synthons in bioactive natural products.…”

“…[153][154][155][156][157][158][173][174][175][176] RAHB-assisted synthesis of b-enaminones by condensation affords an unique product only in the case of symmetrical b-diketones or when the two carbonyl groups show av ery different electrophilicity towards the nucleophile amine. The Z and E isomers of b-enaminones exhibit different chemical reactivities in synthetic and coordination chemistry.…”

Alkaloid Synthesis via Gold‐Catalyzed Carbon‐Carbon Bond Formation Using Enamine‐type Nucleophile

“…Compared to their enolate equivalents, enamines offer unique advantages. On one hand, in modern asymmetric enamine catalysis, a variety of stereoselective carbon‐carbon bond‐forming reactions of carbonyl compounds could be implemented only by using catalytic amounts of chiral primary amine, or chiral secondary amine ,,. On the other hand, in transition metal catalysis, the reactivities of enamines can be tuned by flexible introduction of substituents either on the nitrogen atom,, or the double bond of enamine motif ,,…”