Chiral Primary Amine/Ketone Cooperative Catalysis for Asymmetric α-Hydroxylation with Hydrogen Peroxide

Abstract

Carbonyl and amine are yin and yang in organocatalysis that mutually activate and transform each other. As intrinsically reacting partners, carbonyl and amine tend to condensate, depleting their individual activity when employed as catalysts. Though widely established as prominent catalytic strategies, aminocatalysis and carbonyl catalysis seems not coexist well and a cooperative amine/carbonyl dual catalysis remains virtually unknown. Here we report a cooperative primary amine and ketone dual catalysis in the asymmetric αhydroxylation with H2O2. Besides participating in the typical enamine catalytic cycle, the chiral primary amine catalyst was found to work cooperatively with a ketone catalyst to activate H2O2 via an oxaziridine intermediate derived from in-situ generated ketimine intermediate. The resulted enamine-oxaziridine coupling then facilitated highly-controlled hydroxylation of β-ketocarbonyls that are not possible with other catalytic methods. The dual catalytic approach allows for highly enantioselective α-hydroxylation of a broad range of β-ketocarbonyls. Particularly, late-stage hydroxylation for peptidyl amide or chiral esters can also 2 be achieved with high stereoselectivity. With its operational simplicity and mild conditions, this cooperative amine/ketone catalysis provides a new strategy in catalytic activation of H2O2 and expands the domain of typical amine and carbonyl catalysis to include those challenging transformations.

Synergistic Strategies in Aminocatalysis

“…The authors applied this strategy in an enamine/ carbonyl synergistic transformation achieving the desired oxygenated product 53, providing a quaternary stereocenter in excellent enantioselectivities (Scheme 10). [23] The authors proposed a differentiating catalytic system where the chiral primary amine 54 is involved in both the HOMO-raising activation of the encumbered carbonyl compound and in the activation of the oxidant. In particular, kinetic and DFT studies support H 2 O 2 activation through oxaziridine C formation, generated by the condensation between trifluoro acetophenone and 54.…”

“…The authors applied this strategy in an enamine/carbonyl synergistic transformation achieving the desired oxygenated product 53 , providing a quaternary stereocenter in excellent enantioselectivities (Scheme 10). [23] …”

Amine Organocatalysis of Remote, Chemoselective C(sp3)–H Hydroxylation

“…Employing a combination of an amine catalyst and an aldehyde or ketone in the presence of an oxidant can result in the three-component formation of an oxaziridinium salt (Figure ). In the only prior example of this concept, Yang has demonstrated the proof of principle of this idea for oxaziridinium-mediated epoxidation. , To the best of our knowledge, there are no examples of the application of this concept, nor of amine organocatalysis more broadly, to atom-transfer hydroxylation of unactivated C–H bonds. As part of our ongoing interests in this area, we have initiated an effort to explore the utility of amine catalysis of C–H oxidation in both intermolecular and intramolecular contexts.…”

Recent Progress in Transition-Metal-Catalyzed Asymmetric Reductive Amination

“…Chiral amines are ubiquitous in a broad range of pharmaceuticals, agrochemicals, natural products, and functional materials. − For example, nearly 50% of small-molecule pharmaceuticals among the top 200 drugs by retail sales in 2019 contain an enantiopure aliphatic amine as a key component . Chiral amine moieties are present in approximately 40% of new chemical entities among drugs approved by the United States Food and Drug Administration (FDA) .…”