Catalytic Asymmetric Direct Vinylogous Michael Addition of γ-Aryl-Substituted Deconjugated Butenolides to Nitroolefins and N-Phenylmaleimide

Abstract

Direct asymmetric vinylogous Michael reactions of γ-aryl-substituted deconjugated butenolides with nitroolefins and Nphenylmaleimide are described using bifunctional thiourea derivatives as the catalyst. The resulting butenolide derivatives containing adjacent quaternary and tertiary stereocenters are obtained in good yields (54-90%) and with excellent enantioselectivities (er up to 99:1) and high diastereoselectivities (dr up to >20:1).Owing to their widespread occurrence as substructures in various natural products, butenolides bearing a γ-quaternary stereocenter 1 have been a target of general interest among synthetic chemists. 2 In recent years, a number of reports concerning the stereoselective synthesis of butenolides containing the γ-quaternary stereocenter have appeared in the literature. 3-10 Because of their potential for the direct construction of γ,γ-disubstituted butenolides, γ-substituted deconjugated butenolides have garnered significant attention. However, most of these reports entail either alkyl-or aryl-substituted deconjugated butenolides as a pronucleophile. For example, Alexakis reported the Michael addition reaction of γ-alkyl-substituted deconjugated butenolides to enals using iminium catalysis. 4 Similarly, the catalytic asymmetric vinylogous Mannich-type reaction of α-angelica lactone with aldimines was reported by Feng using a chiral N,N′-dioxide-Sc(III) complex. 5 In the case of the reaction with isatin-derived MoritaBaylis-Hillman carbonates, disclosed by Chen, γ-arylsubstituted deconjugated butenolides were found to be unreactive. 6 To date, the number of reports where both γ-alkyl-and γ-aryl-substituted butenolides have been utilized successfully for the same transformation are very limited. 7,8 Recently, we disclosed the enantioselective vinylogous Michael addition of γ-alkyl-substituted deconjugated butenolide to nitroolefins 9 and N-substituted maleimides 10 with the help of bifunctional organocatalysts I and II, respectively (Scheme 1): Michael adducts containing contiguous quaternary and tertiary stereocenters were obtained with good to outstanding diastereoselectivity and excellent enantioselectivity.Scheme 1 Bifunctional thiourea-catalyzed direct asymmetric vinylogous Michael addition of γ-alkyl-substituted deconjugated butenolides to nitroolefins and maleimides Inspired by these results and with our continued interest in developing new methods for the construction of quaternary stereocenters in a catalytic enantioselective fashion, we explored the compatibility of our protocols with γ-arylsubstituted deconjugated butenolides. Herein we disclose our findings on the asymmetric vinylogous Michael addition of such arylated deconjugated butenolides to nitroolefins and N-phenylmalemide using our previously reported catalysts I and II, respectively. We commenced our studies with the vinylogous Michael addition to nitroolefins (Table 1). When the reaction between γ-phenyl-substituted deconjugated butenolide 1a and -nitrostyrene (2a) was conducted under our previously optimized react...

Recent Advancement on the Organocatalyzed Asymmetric Conjugate Addition using Maleimide as a Potential Substrate

“… [56] The reaction was found to be equally effective for butenolides bearing linear alkyl chains, branched alkyl groups or benzyl substrates. Further it was also extended with γ‐aromatic substituted butenolides [57] . Overall, the reaction proceeded well to produce several γ‐substituent butanolide adducts 62 bearing a quaternary stereogenic centre adjacent to the oxygen with very high yields, diastereoselectivities and enantioselectivities (up to 99 % yield, 18 : 1 d.r.…”

“…Further it was also extended with γ-aromatic substituted butenolides. [57] Overall, the reaction proceeded well to produce several γ-substituent butanolide adducts 62 bearing a quaternary stereogenic centre adjacent to the oxygen with very high yields, diastereoselectivities and enantioselectivities (up to 99 % yield, 18 : 1 d.r. and > 98 % ee).…”

Unravelling the Development of Non-Covalent Organocatalysis in India

“…Michael addition reactions of butenolides 17 with electrophiles 18 using the slightly modified urea catalyst 2H has been reported by Mukherjee’s group (Scheme 33 ). 79 Using this protocol the authors demonstrated the enantioselective vinylogous 1,4-addition of γ-aryl-substituted deconjugated butenolides 17 with nitroolefins 18 . The main reason for the reduced catalyst loading is the presence of a highly reactive aryl group in the deconjugated butenolides.…”