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. (−)-(3S,4R)-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
(+)-(R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one
in >90% yield and ≥99.5% de using N-selectride without the requirement of chromatographic
purification. The (−)-(3S,4R) 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.