Enantioselective aminocatalysis: Michael addition of unactivated ketones to nitroolefins catalyzed by D-fructose derived monofunctional primary amine

Abstract

Organocatalytic asymmetric Michael addition is considered among the most extensively studied, yet challenging stereoselective reactions due to the fact that the electrophilic prochiral carbon in Michael acceptor lies away from stereodirecting groups of the catalyst. Although there is a report on stereoselective organocatalysis in Michael addition employing monofunctional secondary amine, the use of monofunctional primary amine for the said reaction is not reported till date. In fact, no monofunctional aminocatalyst is reported yet for the synthesis γ-nitro carbonyl compounds. Here we report our preliminary results on the enantioselective Michael addition of different ketones to nitro olefins catalysed by monofunctional primary amine (1) derived from d-fructose.

Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions

“…As described in Scheme 1, sugar amines 1 (1,2:4,5-di-O-isopropylidene-3-amino-3-deoxyα-D-fructopyranose) or 2 (1,2:4,5-di-O-isopropylidene-3-amino-3-deoxy-β-D-fructopyranose) prepared from D-fructose [50,51], were converted to the corresponding isothiocyanates (3 and 4) according to the reported procedure [53]. Subsequently, the newly prepared isothiocyanates were coupled with commercially available chiral 1,2-diamines to afford the desired bifunctional thiourea organocatalysts 5 and 6 (Figure 1) in good yields.…”

“…These chiral organic molecules, which were initially developed by Ma and co-workers in 2007 [36], were demonstrated to successfully facilitate reaction between ketone and nitroalkenes with high yields and excellent stereochemical results. In light of these important precedents, as well as our ongoing interest in asymmetric synthesis [50,51], we explored the asymmetric Michael addition reaction of aliphatic ketones and acetylacetone to substituted β-nitrostyrene using a new class of D-fructose-derived bifunctional primary amine-thiourea catalysts.…”

Recent Advances in Organocatalytic Asymmetric Michael Addition Reactions to α, β‐Unsaturated Nitroolefins

“…Mechanistically, the -NH group of the enamine produces anti-product 36 exhibiting a less favourable intermediate B (Scheme 10). [57] In 2017, Tomas Martin and his group synthesized a modified hybrid dipeptide like pyranoid organocatalyst 41 for the development of chiral γ-nitroaldehyde scaffolds 40. The domino Michael addition reaction of different aldehydes 38 and nitroalkenes 39 were furnished the corresponding Michael products 40 in excellent yield and stereoselectivity.…”

Growing Impact of Carbohydrate‐Based Organocatalysts

“…[79] Another good example of Lewis base catalysis is D-fructose derived monofunctional primary amine [75] catalyzed Michael addition of unactivated ketones to nitroolefins (Scheme 6). [80]…”