Stereoselective synthesis of densely functionalized pyrrolidin-2-ones by a conjugate addition/nitro-Mannich/lactamization reaction.

Copper-catalyzed conjugate addition of diorgano zinc reagents to nitroacrylate 1 followed by a subsequent nitro-Mannich reaction and in situ lactamization leads to an efficient one-pot synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones (5). The versatility of the reaction is shown for a wide range of N-p-(methoxy)phenyl protected aldimines 3 derived from alkyl, aryl, and heteroaryl aldehydes. The densely functionalized pyrrolidin-2-ones 5 are isolated as single diastereoisomers (40 examples, 33-84% yield).

Diastereoselective reductive nitro-Mannich reactions.

A range of nitroalkenes 1 and imines 3 derived from alkyl, aryl, and heteroaryl aldehydes underwent a tandem 1,4-hydride addition nitro-Mannich reaction to afford anti-rich β-nitroamines 4. The crude anti-β-nitroamines 4 could be converted to the corresponding anti-β-nitroacetamides 5 (33 examples) to allow purification in good yield from the parent nitroalkenes (60-87%), and with a high diastereomeric ratio (90:10 to mostly >95:5). A representative selection of anti-β-nitroacetamides 5 (five examples) were reduced to vicinal diamines 7 with zinc hydrochloride; concomitant acyl migration provided differentially protected vicinal diamines 7 in good yield (80-91%).

Enantioselective conjugate addition nitro-Mannich reactions: solvent controlled synthesis of acyclic anti- and syn-β-nitroamines with three contiguous stereocenters.

We report an enantioselective conjugate addition nitro-Mannich reaction protocol which combines dialkylzinc, aromatic nitro alkene and imine to form two C-C bonds and three contiguous stereocenters in one reaction vessel. Absolute stereochemistry was controlled from the initial 1,4-addition of dialkylzinc to aromatic nitroalkenes by known copper-chiral ligand catalysts. The choice of solvent dictated the formation of either the syn,anti or syn,syn diastereoisomers, two of the four possible diastereoisomers.