Asymmetric synthesis of functionalized trifluoromethyl-substituted pyrrolidines via an organocatalytic domino Michael/Mannich [3+2] cycloaddition

Abstract

The asymmetric synthesis of highly functionalized pyrrolidine derivatives with three contiguous stereogenic centers and bearing a trifluoromethyl group has been developed through an organocatalytic domino Michael/Mannich [3+2] cycloaddition sequence. Employing a commercially available secondary amine as the catalyst, the scalable one-pot protocol occurs with high yields and excellent stereoselectivities, providing a short entry into a series of trifluoromethylated pyrrolidines with potential medical value.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[42] Enders and co-workers also achieved the stereoselective synthesis of trifluoromethyl-substituted pyrrolidines 48 using ad omino Michael/Mannich cyclization reactionb etween the a,b-unsaturated aldehydes 42 andt he trifluoromethyl-substituted iminomalonates 47.U sing the secondary amine (S)-45 as the catalyst, products 48 were obtained in excellent yields and stereoselectivities after reactingt he primary productsw ith the Wittig reagent 46b (Scheme 12). [43] Coeffard, Greck,a nd co-workers demonstrated the desymmetrization of prochiral para-quinamines 49 in the synthesis of hydroindole molecules 50 possessing four stereogenic centers. [44] Thed omino aza-Michael/ Michaelr eactiono f49 and a,b-unsaturated aldehydes 42 promoted by the chiral diphenylprolinol silyl ether catalyst 51 yielded compounds 50 in good to high stereoselectivities (Scheme 13).…”

Bifunctional Thio/Squaramide Catalyzed Stereoselective Michael Additions of Aldehydes to Nitroalkenes towards Synthesis of Chiral Pyrrolidines

“…Interestingly, this reaction in water afforded the product in 89% yield, slightly better diastereoselectivity, and similar enantioselectivity. Squaramide C4 catalyzed the addition of aldehyde 6 c to nitroacrylate 9 b with virtually the same results as catalyst C3 (Table 4, entries [11][12][13]. Surprisingly, the yield of Michael addition product decreased to 65% when catalyzed with thiosquaramide C5, with more acidic protons.…”

“…The yield of adduct 8 ag decreased to 32% when the reaction proceeded without any acid additive. Diastereo-as well as enantioselectivity, were virtually unchanged ( Table 2, entries [8][9][10][11]. The yield of adduct 8 ag decreased even further to 27% when we used catalyst C7 under classical condition (stirring at r.t. for 48 h).…”

“…Asymmetric 1,3‐dipolar cycloaddition reaction of azomethine ylides with alkenes catalyzed by zinc(II) bisoxazolines provided tetrasubstituted chiral pyrrolidines . Highly functionalized pyrrolidine derivatives with three contiguous stereogenic centers and bearing a trifluoromethyl group have been synthesized with high yields and stereoselectivities through an organocatalytic one‐pot domino Michael/Mannich [3+2] cycloaddition sequence using a commercially available secondary amine as the catalyst, Brønsted acid‐catalyzed three‐component asymmetric 1,3‐dipolar cycloaddition between aldehydes, amino esters, and dipolarophiles furnished multiply substituted pyrrolidines . Enantioselective [3+2] cycloaddition of azomethine ylides generated in situ from racemic α‐iminocyanoacetates with α,β‐unsaturated aldehydes catalyzed by diphenyl prolinol gave pyrrolidine cycloadducts with four stereocenters .…”

Recent Advances in Organocatalyzed Domino C–C Bond-Forming Reactions

“…Catalyst 1 has also recently been used to catalyze a Michael/Mannich [3 + 2] cycloaddition cascade reaction between α-β-unsaturated aldehydes and trifluoromethyl-substituted iminomalonates to form trifluoromethyl-substituted pyrrolidines ( Scheme 2 ) [ 20 ].…”