The synthesis of a functionalized derivative containing the 2,8-ethanonoradamantane carbocyclic skeleton, whose key-step consists of an intramolecular Diels–Alder reaction, is described. Chemoselective reduction of an intermediate enone required protection of the maleimide function through their Diels–Alder adducts with furan.

The enantioselective synthesis of the title compound, its conversion into a thiourea-type organocatalyst and the behavior of this organocatalyst in several enantioselective Michael reactions are described.(R)-1,4,4-Trimethyl-3-[(1-phenylethyl)imino]pyrrolidin-2-oneC15H20N2O[α]D24=+62 (c 0.81, CH2Cl2)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (R)(3S,1′R)-1,4,4-Trimethyl-3-[(1-phenylethyl)amino]pyrrolidin-2-one·(S)-mandelateC15H22N2O·C8H8O3[α]D22=+171 (c 0.65, MeOH)Source of chirality: Diastereoselective reduction using (R)-1-phenylethylamine as a chiral auxiliaryAbsolute configuration: (3S,1′R) (S)(3R,1′R)-1,4,4-Trimethyl-3-[(1-phenylethyl)amino]pyrrolidin-2-one·(S)-mandelateC15H22N2O·C8H8O3[α]D22=+148 (c 1.04, MeOH)Source of chirality: Diastereoselective reduction using (R)-1-phenylethylamine as a chiral auxiliaryAbsolute configuration: (3R,1′R) (S)(3S,1′R)-1,4,4-Trimethyl-3-[(1-phenylethyl)amino]pyrrolidin-2-oneC15H22N2O[α]D22=+144 (c 0.74, CH2Cl2)Source of chirality: Diastereoselective reduction using (R)-1-phenylethylamine as a chiral auxiliaryAbsolute configuration: (3S,1′R)(3R,1′R)-1,4,4-Trimethyl-3-[(1-phenylethyl)amino]pyrrolidin-2-oneC15H22N2O[α]D22=+139 (c 1.10, CH2Cl2)Source of chirality: Diastereoselective reduction using (R)-1-phenylethylamine as a chiral auxiliaryAbsolute configuration: (3R,1′R)(S)-3-Amino-1,4,4-trimethylpyrrolidin-2-oneC7H14N2O[α]D22=+41 (c 0.90, CH2Cl2)Source of chirality: Diastereoselective synthesis using (R)-1-phenylethylamine as a chiral auxiliaryAbsolute configuration: (S)(S)-3-Amino-1,4,4-trimethylpyrrolidin-2-one mono-O,O-di-p-toluoyl-(2R,3R)-tartrateC7H14N2O·C20H18O8[α]D22=-106 (c 0.54, MeOH)Source of chirality: Diastereoselective synthesis using (R)-1-phenylethylamine as a chiral auxiliaryAbsolute configuration: (S) (2R,3R)(S)-(1,4,4-Trimethylpyrrolidin-3-yl)amine dihydrochlorideC7H16N2·2HCl[α]D22=-12 (c 1.03, H2O)Source of chirality: Diastereoselective synthesis using (R)-1-phenylethylamine as a chiral auxiliaryAbsolute configuration: (S)(S)-(1,4,4-Trimethylpyrrolidin-3-yl)amineC7H16N2[α]D23=-3 (c 0.73 CH2Cl2)Source of chirality: Diastereoselective synthesis using (R)-1-phenylethylamine as a chiral auxiliaryAbsolute configuration: (S)(S)-N-1,4,4-Trimethylpyrrolidin-3-yl-N′-[3,5-bis(trifluoromethyl)phenyl]thioureaC16H19N3F6S[α]D25=-23 (c 0.53, CH2Cl2)Source of chirality: Diastereoselective synthesis using (R)-1-phenylethylamine as a chiral auxiliaryAbsolute configuration: (S)

An easy access to both enantiomers of 3-amino- and 3-(dimethylamino)-4,4-dimethylpyrrolidin-2-one from rac-pantolactam using (R)-α-methylbenzylamine as a chiral auxiliary is described.(R)-1-(p-Methoxybenzyl)-4,4-dimethyl-3-[(1-phenylethyl)imino]pyrrolidin-2-oneC22H26N2O2[α]D23=+39 (c 0.76, CH2Cl2)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (R)(3S,1′R)-1-(p-Methoxybenzyl)-4,4-dimethyl-3-[(1-phenylethyl)amino]pyrrolidin-2-one·(2R,3R)-tartrateC22H28N2O2·C4H6O6[α]D23=+9 (c 1.10, MeOH)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (3S,1′R)(2R,3R)(3S,1′R)-1-(p-Methoxybenzyl)-4,4-dimethyl-3-[(1-phenylethyl)amino]pyrrolidin-2-oneC22H28N2O2[α]D23=+14 (c 0.54, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (3S,1′R)(S)-3-Amino-1-(p-methoxybenzyl)-4,4-dimethylpyrrolidin-2-oneC14H20N2O2[α]D23=-43 (c 0.90, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)(S)-3-Amino-1-(p-methoxybenzyl)-4,4-dimethylpyrrolidin-2-one·mono-(2R,3R)-O,O′-di-(p-toluoyl)tartrateC14H20N2O2·C20H18O8[α]D23=-117 (c 0.95, MeOH)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)(2R,3R)(S)-3-(Dimethylamino)-1-(p-methoxybenzyl)-4,4-dimethylpyrrolidin-2-oneC16H24N2O2[α]D23=-76 (c 0.58, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)(S)-3-(Dimethylamino)-1-[(3-hydroxymethyl)-4-methoxybenzyl]-4,4-dimethylpyrrolidin-2-oneC17H26N2O3[α]D23=-40 (c 0.59, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)(S)-3-(Dimethylamino)-1-(p-methoxybenzyl)-4,4-dimethylpyrrolidin-2-one·mono-(2R,3R)-O,O′-di-(p-toluoyl)tartrateC16H24N2O2·C20H18O8[α]D23=-105 (c 0.79, MeOH)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)(2R,3R)Benzyl (S)-N-[1-(p-methoxybenzyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl]carbamateC22H26N2O4[α]D23=+25 (c 0.62, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)Benzyl (S)-N-[1-(p-methoxybenzyl)-4,4-dimethyl-2,5-dioxopyrrolidin-3-yl]carbamateC22H24N2O5[α]D23=-28 (c 0.46, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)Benzyl (S)-N-[4,4-dimethyl-2-oxopyrrolidin-3-yl]carbamateC14H18N2O3[α]D23=-12 (c 0.30, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)(S)-3-Amino-4,4-dimethylpyrrolidin-2-oneC6H12N2O[α]D23=-17 (c 0.53, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)(R)-4,4-Dimethyl-3-[(1-phenylethyl)imino]pyrrolidin-2-oneC14H18N2O[α]D23=+44 (c 0.80, CH2Cl2)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (R)(3S,1′R)-4,4-Dimethyl-3-[(1-phenylethyl)amino]pyrrolidin-2-oneC14H20N2O[α]D23=+26 (c 1.30, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (3S,1′R)(3R,1′R)-4,4-Dimethyl-3-[(1-phenylethyl)amino]pyrrolidin-2-oneC14H20N2O[α]D23=+136 (c 0.70, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (3R,1′R)(S)-3-(Dimethylamino)-4,4-dimethylpyrrolidin-2-oneC8H16N2O[α]D23=-20 (c 0.78, CH2Cl2)Source of chirality: diastereoselective reduction using (R)-1-phenylethylamineAbsolute configuration: (S)

A novel series of donepezil−tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced Aβ aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant Aβ antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.

The synthesis of levetiracetam and its enantiomer by deracemization of (±)-2-bromobutyric acid using either (S)- or (R)-N-phenylpantolactam as chiral auxiliaries, followed by SN2 substitution of the bromine atom by a 2-oxopyrrolidin-1-yl group and amidation of the carboxylic acid, is described.(αS,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-(2-oxopyrrolidin-1-yl)butyrateC20H26N2O4Dr > 98:2Ee > 99%[α]D20=-42.3 (c 0.96, CHCl3)Source of chirality: (S)-N-phenylpantolactamAbsolute configuration: αS,3S(αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-(2-oxopyrrolidin-1-yl)butyrateC20H26N2O4Dr > 98:2Ee > 99%[α]D20=+50.3 (c 1.03, CHCl3)Source of chirality: (S)-N-phenylpantolactamAbsolute configuration: αR,3S(αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-chlorobutyrateC16H20ClNO3Dr = 85:15Ee > 99%Source of chirality: (R)-N-phenylpantolactamAbsolute configuration: αS,3R(αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-bromobutyrateC16H20BrNO3Dr > 98:2Ee > 99%[α]D20=-36.6 (c 1.19, CHCl3)Source of chirality: (S)-N-phenylpantolactamAbsolute configuration: αR,3S