Chemoenzymatic Synthesis of Optically Active Ethereal Analog of iso -Moramide-A Novel Potentially Powerful Analgesic †.

To develop potent and safer analgesics, we designed and synthesized a novel enantiomerically enriched ethereal analog of ( R )- iso -moramide, namely 2-[(2 R )-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one. The titled active agent can potentially serve as a powerful synthetic opiate with an improved affinity and selectivity toward opioid receptors (ORs). This hypothesis was postulated based on docking studies regarding the respective complexes between the designed ligand and µ -OR, δ -OR, and κ -OR. The key step of the elaborated asymmetric synthesis of novel analog involves lipase-catalyzed kinetic resolution of racemic 1-(morpholin-4-yl)propan-2-ol, which was accomplished on a 10 g scale via an enantioselective transesterification employing vinyl acetate as an irreversible acyl donor in tert -butyl methyl ether (MTBE) as the co-solvent. Next, the obtained homochiral ( S )-(+)-morpholino-alcohol (>99% ee) was functionalized into corresponding chloro-derivative using thionyl chloride (SOCl 2 ) or the Appel reaction conditions. Further transformation with N -diphenylacetyl-1-pyrrolidine under phase-transfer catalysis (PTC) conditions using O 2 -saturated DMSO/NaOH mixture as an oxidant furnished the desired levorotatory isomer of the title product isolated in 26% total yield after three steps, and with 89% ee. The absolute configuration of the key-intermediate of ( R )-(-)- iso -moramide was determined using a modified form of Mosher's methodology. The preparation of the optically active dextrorotatory isomer of the titled product (87% ee) was carried out essentially by the same route, utilizing ( R )-(-)-1-(morpholin-4-yl)propan-2-ol (98% ee) as a key intermediate. The spectroscopic characterization of the ethereal analog of iso -moramide and the enantioselective retention relationship of its enantiomers using HPLC on the cellulose-based chiral stationary phase were performed. Moreover, as a proof-of-principle, single-crystal X-ray diffraction (XRD) analysis of the synthesized 2-[(2 R )-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one is reported.