Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University of Munich, Munich, Germany.
Department of Chemistry, Ludwig-Maximilians University of Munich, Munich, Germany.
Arch Pharm (Weinheim). 2022 Feb;355(2):e2100362. doi: 10.1002/ardp.202100362. Epub 2021 Nov 5.
Two independent chiral pool syntheses of both enantiomers of the TRPML inhibitor, trans-ML-SI3, were developed, starting from commercially available (1S,2R)- and (1R,2S)-configured cis-2-aminocyclohexanols. Both routes lead to the target compounds in excellent enantiomeric purity and good overall yields. For the most attractive (-)-trans-enantiomer, the R,R-configuration was identified by these unambiguous syntheses, and the results were confirmed by single-crystal X-ray structure analysis. These effective synthetic approaches further allow flexible variation of prominent residues in ML-SI3 for future in-depth analysis of structure-activity relationships as both the piperazine and the N-sulfonyl residues are introduced into the molecule at late stages of the synthesis.
两种独立的手性池合成方法，从商业可得的（1S,2R）-和（1R,2S）-构型的顺式-2-氨基环己醇出发，分别对 TRPML 抑制剂反式-ML-SI3 的两种对映异构体进行了开发。两条路线都以优异的对映体纯度和良好的总收率得到目标化合物。对于最有吸引力的（-）-反式对映异构体，通过这些明确的合成方法确定了 R,R-构型，并且通过单晶 X 射线结构分析证实了结果。这些有效的合成方法进一步允许在 ML-SI3 中灵活改变突出残基，以便将来对结构-活性关系进行深入分析，因为在合成的后期将哌嗪和 N-磺酰基残基引入到分子中。
