Synthèse d'homologues de la (–)‐‐(1R,2S)‐norephedrine

Abstract

Synthesis of (–)‐(1R,2S)‐Norephedrine Homologues The amino function of esters of some simple natural amino acids I is blocked in the form of a cyanoenamine by means of 2‐oxocyclopentanecarbonitrile, so that the corresponding cyanoenamino esters II are obtained. The reaction of a disubstituted lithium amide with II leeds to the cyanoenamino‐amides VI. The amide function present in VI is then transformed into an aromatic ketone by means of phenyllithium, to give the (benzoylalkyl)aminocyclopentenecarbonitriles VII. Reduction of Compounds VII with NaBH4 in EtOH −80° affects only the keto function and leads to the [(α‐hydroxybenzyl)alkyl]amino‐cyclopentenecarbonitriles VIII. The amino function is then deprotected by acid hydrolysis to give the amino‐alcohols IX with yields close to 50%; in every amino‐alcohol IX, the erythro isomer, homologous to natural (–)‐(1R,2S)‐norephedrine is the more abundant or the single product. All the polyfunctional compounds prepared conserve optical activity; it has been demonstrated that the amino‐alcohols IX are pure enantiomers and that no racemisation lakes place at any step of their synthesis.

A New Approach to the Synthesis of Optically Active Norephedrine, Norpseudoephedrine and Cathinone via Double Asymmetric Induction

“…24% yield; R f 0.24 (eluent: EtOAc/hexane 1 : 2); white solid; mp 61-62 o C; IR (KBr, cm −1 ) 3421, 3303, 1690, 1542; 1 H NMR (200 MHz, CDCl 3 ) δ 1.11 (3 H, d, J = 6.7, CH 3 ), 2.89 (1 H, br s, NH), 3.95 (1 H, m, CHNH), 4.59 (1 H, d, J = 5.5, OH), 5.00 (1 H, d, J = 7.9, CHOH), 5.05 (2 H, s, PhCH 2 ), 7.25-7.35 (10 H, m, ArH); 13 C NMR (50 MHz, CDCl 3 ) δ 18.32 (CH 3 ), 36.93 (CHNH), 53.43 (PhCH 2 ), 67.45 (CHOH), 127.19, 128.79, 129.17, 137.16, 142.06 (Ar-C), 157.31 (NHCO); HPLC analysis showed it to be 93% ee with the (1R,2R)-configuration [t R (1S,2S) 55.08 min and t R (1R,2R) 57.62 min];= 37.60 (c 1.35, CHCl 3 ).Preparation of (1R,2S)-norephedrine (1R,2S)-1 from 8a.To a solution of 8a with 96% ee (1 mmol) in EtOAc (4 mL) was added 3 N HCl solution (2 mL) and stirred at room temperature for 1 h. The mixture was basified with 6 N NaOH solution and extracted with CH 2 Cl 2 (3 × 5 mL). The combined extract was dried over anhydrous Na 2 SO 4 , filtered, concentrated and crystallized with ether-hexane to give (1R,2S)-1 in 90% yield; white solid; mp 49-51 o C (lit 22. 51-52 o C); IR (KBr, cm −1 ) 3338, 3063, 1605, 1452; 1 H NMR (200 MHz, CDCl 3 ) δ 0.75 (3 H, d, 3H, J = 6.7, CH 3 ), 2.40 (3 H, br s, NH 2 + OH), 3.13 (1 H, quintet, J = 5.7, CHNH 2 ), 4.50 (1 H, d, J = 4.6, CHOH), 7.23-7.37 (5 H, m, ArH); 13 C NMR (50 MHz, CDCl 3 ) δ 18.62 (CH 3 ), 52.64 (CHNH 2 ), 77.06 (CHOH), 127.23, 128.11, 128.85, 142.16 (Ar-C); HPLC analysis of 8a obtained from treatment of this product with Boc 2 O showed it to be 96% ee; = -14.71 (c 1.83, EtOH){lit.…”