Laboratory of Biocatalysis and Biotransformation, Department of Drugs Technology and Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Koszykowa St. 75, 00-662 Warsaw, Poland.
Int J Mol Sci. 2022 Oct 5;23(19):11803. doi: 10.3390/ijms231911803.
To develop potent and safer analgesics, we designed and synthesized a novel enantiomerically enriched ethereal analog of (R)-iso-moramide, namely 2-[(2R)-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 (SOCl2) or the Appel reaction conditions. Further transformation with N-diphenylacetyl-1-pyrrolidine under phase-transfer catalysis (PTC) conditions using O2-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-[(2R)-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one is reported.
为了开发高效且安全的镇痛药，我们设计并合成了（R）-异吗罗定的新型对映体富集的醚类类似物，即 2-[(2R)-2-(吗啉-4-基)氧基]-2,2-二苯基-1-(吡咯烷-1-基)乙-1-酮。该活性药物有望成为一种具有强大的合成阿片类药物，对阿片受体（ORs）具有更高的亲和力和选择性。这一假设是基于对设计配体与 µ-OR、δ-OR 和 κ-OR 各自复合物的对接研究提出的。所阐述的新型类似物的不对称合成的关键步骤涉及脂肪酶催化的外消旋 1-（吗啉-4-基）-2-丙醇的动力学拆分，该拆分是通过在叔丁基甲醚（MTBE）中使用不可逆酰基供体醋酸乙烯酯进行对映选择性转酯化，在 10 g 规模上完成的。然后，通过使用 O2-饱和的 DMSO/NaOH 混合物作为氧化剂的相转移催化（PTC）条件，将得到的手性（S）-（+）-吗啉醇（>99%ee）转化为相应的氯代衍生物，用氯化亚砜（SOCl2）或 Appel 反应条件。然后在相转移催化（PTC）条件下，用 N-二苯甲酰基-1-吡咯烷进行进一步转化，使用 O2-饱和的 DMSO/NaOH 混合物作为氧化剂，得到所需的标题产物的左旋异构体，三步总收率为 26%，ee 值为 89%。使用改进的 Mosher 方法确定了（R）-（-）-异吗罗定的关键中间体的绝对构型。标题产物的右旋异构体（87%ee）的制备基本上通过相同的路线进行，使用（R）-（-）-1-（吗啉-4-基）-2-丙醇（98%ee）作为关键中间体。使用纤维素手性固定相在高效液相色谱（HPLC）上对异吗罗定的醚类类似物进行了光谱表征，并对其对映异构体的对映选择性保留关系进行了研究。此外，作为原理验证，还报道了所合成的 2-[(2R)-2-(吗啉-4-基)氧基]-2,2-二苯基-1-(吡咯烷-1-基)乙-1-酮的单晶 X 射线衍射（XRD）分析。
