Catalytic, enantioselective vinylogous Michael reactions

Abstract

Recent progress in the field of catalytic, enantioselective vinylogous Michael reactions of latent dienolates is described which furnish optically highly enriched chiral 1,7-dioxo compounds of great utility in one synthetic operation. Emphasis is given to new catalysis modes which realise this challenging transformation with high regio- as well as enantioselectivity.

Exploiting the Distal Reactivity of Indolyl Methylenemalononitriles: An Asymmetric Organocatalyzed [4+2] Cycloaddition with Enals Enables the Assembly of Elusive Dihydrocarbazoles

“…In particular, it is reasonable to assume that initial formation of the indole o-quinodimethane A and iminium ion B from the respective malononitrile 1a and aldehyde 2a takes place under the assistance of the binaryp rolinol/(iPr) 2 NEt catalytic system. The chirale nvironment in the resultingd onor/acceptor complex AB allows the subsequent bis-vinylogousM ichael attack [12] to proceed stereoselectively,f orming the chiral enamine C.N ext, this intermediate undergoes an intramolecular Michael ring closure to form substituted tetrahydrocarbazole D which,u pon hydrolysis andr elease of both the catalysta nd the malononitrile handle, [5,13] finally furnishes the (R)-configured dihydrocarbazole 3aa.…”

Catalyst‐Enabled Site‐Divergent Stereoselective Michael Reactions: Overriding Intrinsic Reactivity of Enynyl Carbonyl Acceptors

“…[2][3][4][5] One of the synthetically relevant carbon-carbon bond formations that are associated with this innate selectivity problem is the Michael addition of prochiral enolates to extended conjugate systems,s uch as dienyl carbonyl compounds.V arious strategies have been introduced to control the reaction site together with relative and absolute stereochemistry. [2][3][4][5] One of the synthetically relevant carbon-carbon bond formations that are associated with this innate selectivity problem is the Michael addition of prochiral enolates to extended conjugate systems,s uch as dienyl carbonyl compounds.V arious strategies have been introduced to control the reaction site together with relative and absolute stereochemistry.…”

“…We then thoroughly explored the scope with repsepct to the azlactones 3 in the 2i-catalyzed asymmetric 1,6-addition to 4.T he results listed in Table 2show that the incorporation of various alkyl and aryl groups onto the 4-position of 3 was tolerated and 1,6-g-Z,E-5 products were predominantly obtained with high stereoselectivities (entries [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. It should be noted that lowering the temperature to À40 8 8C was crucial for the additions of N-Ts-tryptophan-and phenylglycine-derived azlactones 3h and 3i,respectively,toproceed with rigorous enantiocontrol (entries 13 and 14).…”

“…When this regiochemical consideration is coupled with as tereochemical issue in ag eneral synthetic context, simultaneous dictation of both the selectivities poses am ore profound challenge,p articularly in catalytically directing the bond-forming reactions that involve multiple stereoselectivity factors. [2][3][4][5] One of the synthetically relevant carbon-carbon bond formations that are associated with this innate selectivity problem is the Michael addition of prochiral enolates to extended conjugate systems,s uch as dienyl carbonyl compounds.V arious strategies have been introduced to control the reaction site together with relative and absolute stereochemistry. [6,7] However, catalyst-dependent switching of the reaction site with preservation of the rigorous stereocontrol has,t od ate,p roved elusive despite offering an expedient means to access structurally distinct yet stereochemically homogeneous conjugate adducts from as ingle set of sub- strates.T his situation shows that regiochemical control still heavily relies on the exploitation of the intrinsic reactivity preference of the employed substrates,especially in attaining selectivity at aremote terminal site of the conjugated acceptor.…”

An Asymmetric Vinylogous Michael Cascade of Silyl Glyoximide, Vinyl Grignard, and Nitroalkenes via Long Range Stereoinduction

“…Although the vinylogous Mukaiyama aldol 1 and Mannich 2 reactions have become well-established, the vinylogous Michael reaction has received less attention. 3 A key selectivity issue is the site of trapping in the extended π-system. Computational studies of frontier orbital densities and HOMO coefficients of simple lithium metallodienolates have established that α-trapping is favored over the γ-position.…”