Organocatalytic Asymmetric Aziridination of Enones

Abstract

The development of novel and efficient catalytic methodologies for the stereoselective preparation of chiral aziridines is an important synthetic target.[1] Aziridines constitute a key structural feature of several classes of natural products and are extremely versatile building blocks that can undergo synthetically useful transformations.[2] The catalytic asymmetric aziridinations of olefins provide direct and useful access to such a valuable scaffold, and great efforts and progress have been made in this field.[3] However, to our knowledge, a general and highly stereoselective aziridination of simple a,b-unsaturated enones is still lacking. [4,5] Herein, we report an organocatalytic solution to this synthetic problem that is founded upon the use of a readily available chiral primary amine catalyst salt as well as on a rationally designed N-centered nucleophile.Previously reported asymmetric aziridinations of enones have severe restrictions in scope, as only chalcones are suitable substrates: metal-based systems [4] can provide highly enantioenriched compounds protected as N-tosyl derivatives, a protecting group that can prove to be difficult to remove, whereas two ingenious organocatalytic entries to nonprotected aziridines, showing moderate enantioselectivity (up to 67 % ee), were recently reported through the use of chiral tertiary amines. [5] Recently, the spectacular advances achieved in the field of chiral secondary amine catalysis [6] have set the conditions for the development of a highly chemo-and stereoselective aziridination of a,b-unsaturated aldehydes. [7] Central to the success of this approach was the ability of the organocatalyst to integrate orthogonal activation modes (iminium ion and enamine catalysis) into a more elaborate reaction sequence, [8] thus promoting first the nucleophilic addition of a N-centered nucleophile followed by an intramolecular cyclization (Scheme 1). We sought to extend this organocatalytic strategy to a,b-unsaturated ketones, an idea that was mainly triggered by the recent applications of chiral primary amine salts as efficient activators of enones through iminium catalysis.[9] The reduced steric constraints of primary amines offers the unique possibility of catalyzing processes between sterically demanding partners, overcoming the inherent difficulties of chiral secondary amine catalysis.In particular, we recently introduced the catalyst primary amine salt 1, [10] which is made by combining the easily available 9-amino(9-deoxy)epi-hydroquinine 2 with d-N-Boc phenylglycine (3; Boc = tert-butyloxycarbonyl). Salt 1 exhibits high reactivity and selectivity in the enantioselective conjugate additions of carbon-,[10a] oxygen-, [10b] and sulfurcentered [10c] nucleophiles to a,b-unsaturated ketones.To consolidate salt 1 as a general and selective iminium catalyst for enones, we questioned whether this catalytic system might be successfully extended to the highly enantioselective amine conjugate addition, a primary strategy for C À N bond construction. [11] Prompted by the s...

Asymmetric Organocatalytic Reactions of α,β-Unsaturated Cyclic Ketones

“…The authors claim the most interesting feature of this reaction is that, conversely from most of the reactions described in this review, the catalytic couple is not formed by an amine and an acid, but by two amines. A couple between a Cinchona alkaloid derivative and an aminoacid has already been used by other research groups and examples have also been reported in this review, too [63,81,85,86]. However, in previous reports, Cinchona alkaloid derivatives act as the catalysts and drive the enantioselectivity, whereas aminoacid sometimes improves the general efficiency of the catalyst trough matched/mismatched combinations.…”

“…Moreover, the catalyst for the reaction is an amino acid-Cinchona alkaloid salt and both the pseudo-enantiomers of the catalyst (73 and 73', the same as 56 with different counterions) are available, so both optical antipodes of the aziridine can be prepared (Scheme 21) [85,86].…”

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

“…To the best of our knowledge, such a reaction for this class of compounds has not yet been described. As mentioned previously, the organocatalytic aziridination of cyclic enones has only been rarely described, whereas acyclic enones have been studied more frequently (35,36). Differently substituted hydroxylamine derivatives were tested as nucleophilic reagents, in which the hydroxy functionality serves as the leaving group and enables therefore the formation of the three-membered heterocycle after the nucleophilic 1,4-addition of the amine moiety.…”

“…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).…”

Recent Advances on the Organocatalyzed Enantioselective α-heterofunctionalization of Carbonyl Compounds

“…Salt 12 (20 mol%) was able to promote the aziridination of aliphatic and aromatic α,β-unsaturated ketones, using tosylated carbamate 11a and NaHCO 3 as base at room temperature, yielding the corresponding aziridines 13 in high yields, diastereo-and enantioselectivities (Scheme 3) [18]. The reaction seemed to be tolerant to steric and electronic demands on the starting poor olefin systems.…”