Asymmetric organocatalysis has become a field of central importance for the stereoselective preparation of chiral, enantioenriched molecules. [1] In particular, chiral secondary amine catalysis has proven to be a powerful procedure for the enantioselective transformation of carbonyl compounds. Aminocatalysis has enabled the asymmetric a-, b-, and gfunctionalization of aldehydes and ketones with a wide range of electrophiles and nucleophiles by exploiting catalytic enamine, [2] SOMO (singly occupied molecular orbital), [3] iminium ion, [4] and dienamine [5] activation modes (Scheme 1). Within the realm of the non-inert elements classified as "non-metals" in the periodic table, only selenium-based compounds have yet to be stereoselectively incorporated into carbonyl compounds by organocatalysis.[6]Herein we report the exploitation of the enamine activation strategy in the first highly enantioselective aselenenylation of aldehydes catalyzed by a readily available chiral secondary amine. [7] This process provides access to highly attractive a-seleno aldehydes in high yield and with excellent enantiomeric excess (95-99 %) from commercially available starting materials under mild and simple reaction conditions. The synthetic utility of such intermediates [8] is demonstrated by their easy and rapid conversion into valuable chiral building blocks.The only access to chiral a-seleno aldehydes reported to date relies on a "chiral-pool" approach that involves multistep procedures.[9] To the best of our knowledge, no catalytic enantioselective processes are available for the preparation of these optically active building blocks. In light of this, and considering our recent efforts to expand the scope of asymmetric aminocatalysis, [10] we wondered whether the enamine activation concept might be extended to the highly enantioselective addition of selenium-based compounds to aldehydes.To assess the feasibility of such an asymmetric organocatalytic a-selenenylation strategy, we focused on air-stable, commercially available N-(phenylseleno)phthalimide (2) as the electrophilic selenium source.[11] Thus, treatment of propanal (1 a) with 2 in the presence of 10 mol % of l-proline in CH 2 Cl 2 (0.5 m) resulted in a clean but poorly selective selenenylation of the aldehyde (Table 1, entry 1). We then turned our attention to the use of imidazolidinone A [12] and the diarylprolinol silyl ethers B and C (TMS = trimethylsilyl), [13] which have recently emerged as potentially general enamine organocatalysts for a broad range of highly selective a-functionalizations of aldehydes.

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...

Spirocyclic compounds are attractive targets in organic synthesis because of their broad distribution in biologically active natural products and pharmaceuticals, [1] as well as their increasing use in a range of important chemical and technological processes, such as asymmetric synthesis and organic optoelectronics.[2] On this basis the development of novel methods for the construction of spirocyclic frameworks is of considerable importance, particularly when these methods give rise to the enantioselective formation of an all-carbon quaternary stereocenter, which itself is considered to be a challenging transformation. [3,4] Over the past decade, extensive work on organocatalyzed asymmetric conjugated additions of trisubstituted carbon nucleophiles to electron-deficient alkenes demonstrated that these reactions represent an attractive solution to the problem of selectively generating quaternary stereocenters.[4] Recently several organocatalytic cascade processes involving Michael additions have been successfully applied to the synthesis of spirocyclic compounds.[5] These methods, are based on Michael or Michael/ aldol-type sequences and provide access to spiro-oxindoles, spirobenzofuranones, or spiro-3,4-dihydropyrans with high stereocontrol. The use of novel substrate combinations and the development of new cascade or one-pot reactions are significant advances in this field, thus making the asymmetric assembly of structurally diverse spirocyclic compounds possible from simple and readily available precursors. In this field and in continuation of our efforts to expand the scope of privileged organocatalysts in the field of selenium chemistry, [6,7] we herein report the first highly enantioselective synthesis of spirolactones starting from racemic cyclic bketoesters and the vinyl selenone catalyzed by bifunctional cinchona-alkaloid-derived catalysts. The operationally simple, one-pot Michael addition/cyclization sequence is based on the peculiar properties of the phenylselenonyl substituent, which plays a dual role as an electron-withdrawing group, during the addition step, and as a leaving group, during the cyclization by intramolecular nucleophilic substitution.Initial studies were performed with an excess of the tertbutyl b-ketoester 1 a and the easily available vinyl selenone 2 in toluene in the presence of a catalytic amount of anhydrous Na 2 CO 3 (Scheme 1). The formation of the Michael intermediate 3 a was clearly demonstrated by1 H, 13 C, and 77 Se NMR spectra of the crude reaction mixture. Particularly indicativeare the 13 C peak at d = 56 ppm, characteristic of a methylene linked to a selenonyl group, [6b, 8] and the 77 Se signal at d = 994 ppm typical of a phenyl alkyl selenone.[9] This signal is deshielded in comparison with that of the starting conjugated selenone 2, for which a signal is seen at d = 961 ppm. We were delighted to observe that the Michael adduct was smoothly converted in 2 hours into the spirolactone 4 a by stirring at room temperature with silica gel. The excellent leaving ability ...

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