The enantioselective methods reported to date for carrying out conjugate additions of carbon-and heteroatom-centered nucleophiles to electron-deficient olefins, using small chiral organic molecules as catalysts, are reviewed.

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The cyclobutane scaffold is a structural motif incorporated into a wide range of naturally occurring products, as well as into transiently generated intermediates in primary and secondary metabolism. [1] Moreover, the reactivity pattern shown by cyclobutanes when exploiting ring strain as a driving force to facilitate novel reactivity has also opened the way for their use as intermediates in the synthesis of complex molecules. [2] However, despite their interest, the development of methodologies for the stereocontrolled synthesis of cyclobutanes has received little attention over the years. [3] In this context, the [2+2] cycloaddition represents one of the most straightforward approaches for the stereoselective construction of this structure with several reported and efficient examples, which rely on the use of chiral ligands, [4] auxiliaries, [5] or Lewis acid catalysts. [6] Within this context, we wondered if aminocatalysis could contribute to this field by facing the challenge of setting up an enantioselective version of a [2+2] cycloaddition reaction between a,b-unsaturated aldehydes and nitroalkenes. We were inspired by recent work by Seebach, Hayashi, and coworkers, [7] and Blackmond and co-workers [8] (Scheme 1) in which kinetic and structural studies of O-trimethylsilyldiphenylprolinol-catalyzed Michael addition of aldehydes to nitroolefins led to the detection of an aminonitrocyclobutane intermediate, which was identified as a resting state for the catalyst. Taking this discovery into account, we hypothesized that enolizable enals could undergo a similar reaction based on the dienamine activation mode [9] where the catalyst would be able to undergo turnover, thus furnishing a final nitrocyclobutane product. In fact, literature precedent exists for the related [2+2] cycloaddition of enamines with electronpoor alkenes, thus showing that this process can occur spontaneously without the need of photochemical activation. [10] In contrast, there is also literature precedent which shows that the reaction of nitroalkenes with enolizable a,bunsaturated aldehydes under dienamine catalysis leads to the exclusive formation of Michael-type adducts through the selective a-functionalization of the dienamine intermediate and therefore no opportunity arises for cyclobutane formation. [11] Herein, we wish to present our initial results on a novel chiral secondary amine catalyzed enantioselective formal [2+2] cycloaddition of enolizable a,b-unsaturated aldehydes with a-hydroxymethyl-substituted nitroalkenes which leads to the formation of cyclobutanes in a single step (Scheme 2). This reaction is in sharp contrast with previously published work which, as already mentioned, shows the preference for dienamine intermediates generated from enals to undergo Scheme 1. a) Previous work: addition to nitroolefins throuh enamine catalysis. b) Working hypothesis: formal [2 + 2] cycloaddition through dienamine catalysis. TMS = trimethylsilyl.Scheme 2. One-step synthesis of cyclobutanes by [2+2] cycloaddition/ hemiacetalization under...

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A very efficient method for performing stereoselective aldol reactions is reported. The reaction of (S, S)-(+)-pseudoephedrine-derived propionamide enolates with several aldehydes yielded exclusively one of the four possible diastereomers in good yields, although transmetalation of the firstly generated lithium enolate with a zirconium(II) salt, prior to the addition of the aldehyde, is necessary in order to achieve high syn selectivity. The so-formed syn-alpha-methyl-beta-hydroxy amides were transformed into other valuable chiral nonracemic synthons such as alpha-methyl-beta-hydroxyacids, esters, and ketones. Finally, a stereocontrolled reduction procedure starting from the so-obtained alpha-methyl-beta-hydroxy ketones has been developed allowing the synthesis of either 1,3-syn- or 1,3-anti-alpha-methyl-1,3-diols in almost enantiopure form by choosing the appropriate reaction conditions.