Enantioselective Organocatalytic Michael Addition of α‐Substituted Cyanoacetates to α,β‐Unsaturated Selenones

Abstract

A novel enantioselective (up to 90% ee) Michael addition of a-substituted cyanoacetates to a,b-unsaturated selenones in the presence of bifunctional urea and thiourea organocatalysts is described. The Michael adducts, containing an allcarbon quaternary stereocenter, are smoothly converted into synthetically useful polyfunctional compounds by taking advantage of the excellent leaving group ability of the selenone group.Keywords: asymmetric organocatalysis; cyanoacetates; Michael addition; selenones; thiourea catalysts In recent years asymmetric organocatalysis has emerged as a practical and powerful tool for the stereoselective preparation of chiral molecules with an impressive number of synthetic applications, also in the field of natural or biologically active compounds. [1,2] Fundamental carbon-carbon bond forming processes, such as the Michael reaction, have been widely investigated. Various catalysts, activating the nucleophile or the electrophile by formation of covalent bonds or weaker interactions, such as ion pairing or hydrogen bonding, have found application for this versatile transformation. [1,2] Among them, the socalled bifunctional catalysts, [2] bearing an hydrogenbond donor group besides a basic site on a chiral scaffold, have received great attention for the enantioselective addition of 1,3-dicarbonyl compounds or their equivalents to electron-deficient alkenes. [1,2] The simultaneous activation of both the nucleophile and the electrophile allows an excellent level of stereocontrol over the addition event. To date nitroalkenes [3] and a,b-unsaturated carbonyl compounds, [4] imides, [5] nitriles [6] or sulfones [7] have been employed as Michael acceptors. The discovery of novel substrate combinations should provide a simple and convenient access to highly functionalized adducts. Our interest in the field of the organoselenium-based asymmetric syntheses [8] prompted us to investigate the addition of carbon-centered nucleophiles to vinyl selenones. Selenones are well recognized intermediates in organic synthesis with peculiar properties in respect to the sulfur analogues. Thus, for instance, the selenonyl group presents an exceptional aptitude to act as a leaving group.[8b-e,9] Herein, we report the first enantioselective addition of a-substituted cyanoacetates to vinyl selenones. The use of these trisubstituted Michael donors in asymmetric conjugate addition represents one of the most attractive solutions to the challenging problem of generating selectively all-carbon quaternary stereocenters. [10] First experiments were effected on the a-phenyl cyanoacetate 2a and the vinyl selenone 3 in toluene. [11] The easily accessible bifunctional catalysts 1a-f reported in Figure 1, containing phenolic (1a), ureidic (1b, 1d and 1e) or thioureidic (1c and 1f) hydrogen donor groups, respectively, have been examined as catalysts. Cinchonine, quinine and the commercially available Cinchona alkaloid derivatives (DHQ) 2 Pyr and (DHQ) 2 AQN, that lack an H-bond donor group, have also been tested for compa...

Organocatalytic Asymmetric Synthesis and Use of Organoselenium Compounds

“…First experiments were carried out on the α-phenyl cyanoacetate 18a and the vinyl selenone 19 with the common ureidic and thiouredic catalysts 17a-e as well as with cinchonine, quinine, and other commercially available cinchona derivatives that lack a H-bond donor group. 18 We found that the cooperation of the urea or thiourea and tertiary amine functionalities is essential for an efficient enantiocontrol. The best results were obtained in toluene at -70°C with the thioureidic catalyst 17e (20 mol%).…”

“…These compounds are easily accessible from the corresponding selenides by oxidation with 3-chloroperbenzoic acid. We focused our attention on the conjugate addition of α-substituted cyanoacetates 18,19 or cyclic β-ketoesters 20 to vinyl selenones and discovered that easily accessible diaminederived ureas or thioureas or C6′-hydroxyl cinchona derivatives ( Figure 1) can accelerate these 1,4-addition reactions, improve yields, and control the stereoselectivity. Chen et al demonstrated that also 2-oxindoles are suitable nucleophiles for enantioselective thiourea-catalyzed additions to vinyl selenones in an ionic liquid.…”

A New Stereoselective Synthesis of Cyclopropanes Containing Quaternary Stereocentres via Organocatalytic Michael Addition to Vinyl Selenones

“…The excellent leaving group properties of this species have been already exploited for other synthetically useful inter-or intramolecular substitutions. [5,6] This first result prompted us to study the sequence in detail and develop a novel one-pot Scheme 1. Formation of the cyclopropane 6aA.…”

“…During our studies on the asymmetric Michael addition of a-substituted cyanoacetates to vinyl selenones catalyzed by ureidic or thioureidic bifunctional catalysts, we observed that the diastereomeric mixture of Michael adducts 4aA and 5aA affords the cyclopropane 6aA as a single isomer by simple treatment with KCN in DMF (Scheme 1). [5] We explained this process as a Krapcho-type deethoxycarbonylation, followed by an intramolecular nucleophilic substitution of the selenonyl moiety by the enolate intermediate. The excellent leaving group properties of this species have been already exploited for other synthetically useful inter-or intramolecular substitutions.…”

“…When the temperature was raised at 50 8C the reaction time was shortened at 48 h, albeit with a loss of selectivity (Table 1, entry 4). It is interesting to point out that an attempt to effect the addition of 2a on the phenyl (E)-2-phenylethenyl sulfone, structurally related to 3A, failed indicating a different behaviour between the sulphur [11,12] and the selenium [5] containing compounds.…”