Densely Substituted l-Proline Esters as Catalysts for Asymmetric Michael Additions of Ketones to Nitroalkenes

Abstract

Homochiral methyl 4-aminopyrrolidine-2-carboxylates are readily obtained by means of asymmetric (3 + 2) cycloadditions between azomethine ylides and nitroalkenes, followed by catalytic hydrogenation of the intermediate 4-nitro cycloadducts. These 4-aminopyrrolidine-2-carboxylate esters belong to the L-series of natural amino acids and catalyze asymmetric Michael additions of ketones to nitroalkenes. However, the enantioselectivity observed with these novel unnatural organocatalysts is opposite to that obtained with L-proline. Since both 4-nitro and 4-amino L-proline esters are efficient organocatalysts of aldol reactions, these results permit to modulate asymmetric quimioselective aldol and conjugate addition reactions.

Application of 1,3‐Dipolar Reactions between Azomethine Ylides and Alkenes to the Synthesis of Catalysts and Biologically Active Compounds

“…DFT calculations [26] on the most relevant transition structures involved in these Michael additions reproduced correctly the trends in enantioselectivity found in the experimental studies. The shape of the transition structures associated with the be- [24] havior of exo-47 and endo-47 showed that the enamine derived from the primary amino group must adopt axial and isoclinal dispositions in (R,1′S)-exo-TS6 and (S,1′R)-endo-TS6, respectively ( Figure 8).…”

“…[24] Although 4-nitroprolines 28 were unable to catalyze Michael reaction between ketones and nitroalkenes, we found that the corresponding amino analogs 46, obtained by catalytic hydrogenation of their nitro precursors 28, catalyzed very efficiently this reaction. [26] As it is shown in Scheme 11, organocatalyst exo-46 generates Michael adducts (2R,1′S)-47 with good to excellent ee's. In contrast, diastereomer endo-46 gives rise to (2S,1′R)-47aa enantiomer, similar to that produced by L-Pro, with somewhat lower ee.…”

“…The distinct organocatalytic behavior of catalysts 28 and 46 permitted to perform selective aldol and Michael additions. [26] Thus, reaction of double electrophile 48 with cyclohexanone 33a in the presence of exo-28aa yielded aldol 49 as the major isomer with good diastereo-and enantiocontrol. Subsequent reaction of this latter compound with cyclohexanone in the presence of exo-46 gave rise to compound anti-50 as the major diastereomer (Scheme 12).…”

“…The distinct organocatalytic behavior of catalysts 28 and 46 permitted to perform selective aldol and Michael additions . Thus, reaction of double electrophile 48 with cyclohexanone 33a in the presence of exo ‐ 28aa yielded aldol 49 as the major isomer with good diastereo‐ and enantiocontrol.…”

Nitroprolinates as Nucleophiles in Michael‐type Additions and Acylations. Synthesis of Enantiomerically Enriched Fused Amino‐pyrrolidino‐[1,2‐a]pyrazinones and ‐diketopiperazines

“…[9] endo-6 Preferentially promoted the polymerization of D-lactide, whereas exo-6 preferentially polymerized L-lactide from a racemic mixture. [10] Michael-type addition of ketones to nitroalkenes [11] and a three component ketoneÀ carboxylic acidÀ nitroalkene cyclization [12] were successfully organocatalyzed by chiral exo-6 b (X = H), providing good to excellent diastereoselections and high enantiomeric ratios. A series of enantiopure tetrasubstituted nitroprolinate surrogates has been designed as scaffolds [ This publication is part of a Special Collection on "Silver Catalysis in Organic Synthesis".…”