Rhodium-Catalyzed Asymmetric 1,4-Addition and Its …
The potent and selective compounds 2 (WAY-163909)and 3 (vabicaserin) are agonists that exhibit high affinity(Ki of ∼10 and 3 nM, respectively)and good efficacy for 5HT2C (EC50 = 8 nM each)and have been characterized extensively in preclinical drug trials.,,−In orderto overcome the synthesis challenge of carbon-11 incorporationfor 2 and 3, [11C]formaldehydewas used in a Pictet–Spengler cyclization.
He graduated from Kyoto University in 1970
The synthesis of vabicaserin analogues bearing a quaternary center or spiro substitution at the 4-position has been studied via a [6π]-acrylanilide cyclization employing flow photochemistry in a mesoscale and microfluidic flow photoreactor. The method is also used to synthesize 4,4′-disubstituted tetrahydroquinolines and, furthermore, enables the first synthesis of (±)--vabicaserin.
Cycloalkenes with exocyclic acceptor substituents still remain challenging substrates for enantioselective rhodium-catalyzed 1,4-addition. Cycloalkene carbonitriles and carboxylates have been investigated, and a highly diastereo- and enantioselective protocol for 1,4-addition to cyclopentene and cycloheptene carbonitrile has been developed. This new asymmetric transformation was subsequently applied in the asymmetric formal synthesis of the drug candidate Vabicaserin.