Catalytic Enantioselective Peroxidation of α,β-Unsaturated Ketones

Abstract

The number of biologically interesting natural products possessing peroxide structure motifs is substantial and still growing. 1 Many peroxy natural products display antitumor, anticancer and anti parasite activities, which are attributed to the propensity of the peroxide to initiate radical reactions in an ironrich environment. 2 Furthermore, peroxide natural products such as artemisinin are clinically important anti malaria drugs. Despite the potential of chiral peroxides as biologically interesting or even clinically important compounds, synthetic methods for the preparation of chiral peroxides are highly limited. 3,4,5,6 In particular efficient catalytic enantioselective peroxidations with simple achiral precursors are urgently needed, yet none are available. In fact only a single example of a chiral auxiliarydirected peroxidation in high diastereoselectivity could be found in the literature. 7 Herein, we wish to report the development of a highly enantioselective peroxidation of α,β-unsaturated ketones with an easily accessible chiral organic catalyst.The base-promoted reaction of α,β-unsaturated ketones 1 with hydroperoxides 2 represents a classic epoxidation reaction. Asymmetric variants of this epoxidation with both chiral metal and organic catalysts have also been reported. 8-13 It is well-established that the epoxide 3 is formed via a two-step mechanism (Scheme 1); nucleophilic addition of the hydroperoxide 2 to 1 followed by an intramolecular nucleophilic substitution of the resulting enolate (5) that breaks the weak peroxide bond. In principle this epoxidation pathway (1 to 3) could be converted into a peroxidation pathway (1 to 6) if 5 could be trapped by protonation, although the overwhelming preference of 5 for the intramolecular nucleophilic substitution is evident from the lack of reported peroxidation of α,β-unsatrated carbonyl compounds.Although chiral amine-catalyzed nucleophilic epoxidations of α,β-unsaturated carbonyl compounds have already been reported, 13 we suspected that a cinchona alkaloid derivative such as 8 14 could not only render the nucleophilic addition of the hydroperoxide 2 to the iminium intermediate 9 enantioselective, but also strongly influence the partitioning of the peroxyenamine intermediate 10 between the epoxidation (10 to 11) and the peroxidation (10 to 12) pathways (Scheme 2). Presumably, due to steric crash and multipoint binding interactions between the peroxyenamine intermediate and the covalently linked cinchona alkaloid, the bond-rotational freedom of the peroxyenamine should be hampered, compared to that of the enolate 5 in Scheme 1. We expected that this conformational rigidity imposed by 8 on the peroxyenamine would diminish its ability to adopt the active conformation by which the nucleophilic enamine moiety is optimally aligned relative to the O-O bond for the nucleophilic attack. This in turn would decelerate the epoxidation. In contrast, with the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript protonated quinuclidine as a prot...

Katalyse mit primären Cinchona‐Aminen zur asymmetrischen Funktionalisierung von Carbonylverbindungen

“…Daraus resultierten hoch chemo-und stereoselektive Additionen von C-, [51] N-, [52] O- [53] und S-Nucleophilen [54] an Enone (Abbildung 4). Viele klassische Kohlenstoffnucleophile wurden in C-CKupplungen auf dem Weg zur Synthese nützlicher chiraler Bausteine verwendet, was die Vielseitigkeit und den Nutzen Cinchona-basierter Methoden aufzeigt.…”

9-Amino-9-Deoxyepicinchona Alkaloids

“…5,6 In List's paper, the C 2 chiral amine salt was employed to convert the substituted cyclohexenones into their corresponding epoxides in good yields and excellent enantioselectivities. It's the first report on the highly asymmetric epoxidation of simple cyclic enones.…”

Simple strategy for synthesis of optically active allylic alcohols and amines by using enantioselective organocatalysis

“…The described reactions are enabled by an enantioselective enone epoxidation/aziridination-Wharton-reaction sequence. While the organocatalytic epoxidation of cyclic and acylic enones has been recently described by List et al (32,33) and Deng et al (34), the organocatalytic aziridination of enones has been mainly limited to acyclic substrates (35,36). We envisioned that a merger of the catalytic enone functionalizations with the hydrazine mediated 1,3-transposition following the Wharton protocol (37) could allow simple access to a broad spectrum of optically active allylic products under metal-free conditions, and preferably in an one-pot process (Scheme 2).…”