Total Synthesis of Rohitukine and Dysoline and Their Anticancer Analogues Flavopiridol and IIIM-290

Rohitukine is a naturally occurring piperidine alkaloid that has led to the discovery of several potent CDK9/T1 inhibitors, including flavopiridol and IIIM-290. (-)-(3<i>S</i>,4<i>R</i>)-1-Methyl-4-(2,4,6-trimethoxyphenyl)-piperidin-3-ol serves as a crucial chiral intermediate in the synthesis of rohitukine and its analogues. In this paper, we describe the asymmetric synthesis of the chiral alcohol through the diastereoselective reduction of (+)-(<i>R</i>)-1-methyl-4-(2,4,6-trimethoxyphenyl)-piperidin-3-one in >90% yield and ≥99.5% <i>de</i> using <i>N</i>-selectride without the requirement of chromatographic purification. The (-)-(3<i>S</i>,4<i>R</i>) diastereomer intermediate was successfully employed for the gram-scale synthesis of rohitukine, flavopiridol, and IIIM-290. Additionally, herein, we report an acid-promoted ring-opening/ring-closure equilibrium process of the rohitukine core, giving thermodynamically more stable regioisomer dysoline. The CDK9/T1 inhibition study indicates that a piperidine ring at the C8 position of the chromone nucleus is crucial, as C6-regioisomers show significantly reduced or no inhibition. The developed method for producing clinically important piperidine alkaloids is straightforward, is scalable, and involves only a few chromatographic purification steps.