A Novel Strategy Towards the Asymmetric Synthesis of Orthogonally Funtionalised 2-N-Benzyl-N-α-methylbenzylamino- 5-carboxymethyl-cyclopentane-1-carboxylic acid.

Abstract

Abstract:The asymmetric synthesis of the orthogonally funtionalised compounds tert-butyl 2-N-benzyl-N-α-methylbenzylamino-5-methoxycarbonylmethylcyclopentane-1-carboxylate and methyl 2-N-benzyl-N-α-methylbenzylamino-5-carboxymethylcyclopentane-1-carboxylate by a domino reaction of tert-butyl methyl (E,E)-octa-2,6-diendioate with lithium N-α-methylbenzyl-N-benzylamide initiated by a Michael addition, subsequent 5-exo-trig intramolecular cyclisation and posterior selective hydrolysis with trifluoroacetic acid is reported.

Step-Economical Access to Valuable Weinreb Amide 2,5-Disubstituted Pyrrolidines by a Sequential One-Pot Two-Directional Cross-Metathesis/Cyclizing Aza-Michael Process

“…Colorless solid (75 mg, 88% yield) (purified by flash chromatography, cyclohexane/EtOAc 4:1); mp 67–68 °C; 1 H NMR (300 MHz, CDCl 3 ) δ 6.83 (2H, m ), 5.75 (2H, d, J = 15.5 Hz), 2.31 (4H, m) 1.46 (18H, s); 13 C NMR (75 MHz, CDCl 3 ) δ 165.2 (Cq), 145.2 (CH), 123.4 (CH), 114.9 (CH), 79.7 (Cq), 29.9 (CH 2 ), 27.6 (CH 3 ). Physicochemical data are in agreement with literature …”

“…Yellowish oil (22 mg, 55% yield) (purified by flash chromatography, cyclohexane/EtOAc 9:1); IR (neat) ν (cm −1 ) 2221, 1620, 1447, 1308, 1261, 1146, 1086; 1 H NMR (300 MHz, CDCl 3 ) δ 6.46 (2H, m), 5.42 (2H, d, J = 10.8 Hz), 2.63 (4H, m); 13 Physicochemical data are in agreement with literature. 25 (2E,6E)-Octa-2,6-diendioic Acid Diethyl Diester 26 (2h). Colorless oil (103 mg, 76% yield) (purified by flash chromatography, cyclohexane/EtOAc 4:1); 1 H NMR (300 MHz, CDCl 3 ) δ 6.93 (2H, dt, J = 15.6 and 6.2 Hz), 5.85 (2H, d, J = 15.6 Hz), 4.18 (4H, q, J = 7.1 Hz), 2.37 (4H, m), 1.28 (3H, t, J = 7.1 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 166.5 (Cq), 147.0 (CH), 122.1 (CH), 60.3 (CH 2 ), 30.5 (CH 2 ), 14.3 (CH 3 ).…”

Synthesis and Modeling of Ezetimibe Analogues

“…We have demonstrated the use of chiral lithium amide (α-methylbenzyl)benzylamide ( R )- or ( S )-2 in different domino reactions [ 9 , 10 , 11 , 12 ]. Firstly, in 1997, we published an asymmetric conjugate addition cyclization of octa-2,6-diendioate I, initiated by a chiral lithium amide, to obtain, stereoselectively, the methyl 2-amino-5-(2-methoxy-2-oxoethyl)cyclopentane-1-carboxylate (II Scheme 1 ), [ 13 , 14 , 15 ] and applied it to the synthesis of ( R ) and ( S )-methyl (2-methoxycarbonylcyclopent-2-enyl)acetate (III and IV) and ( R )- and ( S )-2-(2-hydroxymethylcyclopent-2-enyl)ethanol, useful homochiral synthons for monoterpenes [ 13 ], and to the asymmetric synthesis of all the stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylic acid (V Scheme 1 ) [ 14 , 15 ]. Most recently, we performed a multicomponent domino reaction, yielding VI, which has been applied towards the asymmetric synthesis of cyclopentane[c]pyran core of iridoid natural products (VII Scheme 1 ) [ 16 ].…”

Multicomponent Domino Reaction in the Asymmetric Synthesis of Cyclopentan[c]pyran Core of Iridoid Natural Products

“…Cyclopentane derivative III has been synthesized, as already mentioned, by adding (R)-1 to 2 without a subsequent electrophile addition [35][36][37]. We wanted to introduce an additional carbon atom in the α-position of the alkoxycarbonylmethyl group, so an electrophile was necessary after performing the abovementioned domino reaction in a tandem multicomponent reaction protocol.…”

“…We first published that a chiral lithium amide could initiate an asymmetric conjugate addition cyclization of nona-2,7-diendioate to generate chiral cyclohexane derivatives (Scheme 1, II) [30][31][32][33], and applied it to the synthesis of (1R,5R,9R)-2-azabicyclo-[3.3.1]nonane-9-carboxylic acid (morphanic acid), with a morphan scaffold [34], which was used in the synthesis of a new class of opioid receptor ligands [32]. In the same way, when octa-2,6-diendioate was used we stereoselectively obtained the 2-amino-5-carboxy-methyl-cyclopentane-1-carboxylate skeleton (Scheme 1, III) [35][36][37], and applied it to the synthesis of (R) and (S)-methyl(-methoxycarbonylcyclopent-2-enyl)acetate IV and (R)-and (S)-2-(2-hydroxymethyl-cyclopent-2-enyl)ethanol, useful homochiral synthons for monoterpenes [35] and to the asymmetric synthesis of all the stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylic acid [36]. We have later shown a novel domino reaction: allylic acetate rearrangement stereoselective Ireland-Claisen rearrangement and asymmetric Michael addition [38][39][40][41].…”