Cooperative Dienamine/Hydrogen‐Bonding Catalysis: Enantioselective Formal [2+2] Cycloaddition of Enals with Nitroalkenes

Abstract

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...

Asymmetric Synthesis of Tetrahydroquinolines through a [3+2] Cycloaddition Controlled by Dienamine Catalysis

“…[2] Moreover, the catalytic modes of amines are still under further investigation. [6] More recently, the Jørgensen [7] and Vicario [8] groups independently reported a [2+2] cycloaddition reaction of a,b-unsaturated aldehydes and nitroalkenes through dienamine catalysis (Scheme 1). [4] Although several elegant examples have been made, the synthetic potential of dienamine catalysis seems to be underestimated and only limited progress has been made to date.…”

Cyclobutane and Cyclobutene Synthesis: Catalytic Enantioselective [2+2] Cycloadditions

“…[23] This catalyst was proposed to operate in asimilar manner to that of oxazaborolidine catalysts in that abathochromatic absorption shift occurs upon substrate binding. It was proposed that the catalyst engages in adual hydrogen-bonding interaction with the substrate according to the model (46)i llustrated in Scheme 7.…”

“…Jørgensen [45] and Vicario [46] have independently reported the [2+ +2] cycloaddition of nitroolefins (e.g., 135)a nd enolizable a,b-unsaturated aldehydes (e.g., 134; Scheme 20). [47] Through use of the bifunctional squaramide catalyst 140,Jørgensen and co-workers were able to generate the fully substituted cyclobutane products 136-139 with excellent diastereo-and enantioselectivity.…”

“…[46] Theg enerated lactols 143-146 were formed as 1:1m ixtures of the aand b-anomers,w ith complete control of diastereoselectivity at all other stereogenic centers.T hese reactions were proposed to operate by addition of adienamine intermediate to athiourea-activated nitroalkene.…”

Organocatalytic, Asymmetric [2+2+2] Annulation to Construct Six-Membered Spirocyclic Oxindoles with Six Continuous Stereogenic Centers

“…Over the past few years, the combination of dual catalytic systems into asymmetric one-pot tandem procedures has been paid much attention due to the fact that this could provide effective access to valuable chiral complex structures from simple precursors via sequential processes. Compared with the costly organo/metal dual catalytic system-induced one-pot sequential processes [6][7][8][9][10][11][12][13], organo/organo catalysis is more experimentally simple and environmentally friendly which could support the development of green and sustainable chemistry [14][15][16][17][18][19][20].…”