American Chemical Society
ja8b02865_si_003.cif (405.84 kB)

Asymmetric Aza-Wacker-Type Cyclization of N‑Ts Hydrazine-Tethered Tetrasubstituted Olefins: Synthesis of Pyrazolines Bearing One Quaternary or Two Vicinal Stereocenters

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posted on 2018-05-26, 00:00 authored by Xuezhen Kou, Qihang Shao, Chenghao Ye, Guoqiang Yang, Wanbin Zhang
We have developed an asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins, affording optically active pyrazolines bearing chiral tetrasubstituted carbon stereocenters. This reaction is tolerant to a broad range of substrates under mild reaction conditions, giving the desired chiral products with high enantioselectivities. Generation of two vicinal stereocenters on the CC double bonds was also achieved with high selectivities, a process which has been rarely studied for Wacker-type reactions. A mechanistic study revealed that this aza-Wacker-type cyclization undergoes a syn-aminopalladation process. It was also found that for substrates bearing two linear alkyl substituents on the outer carbon atom of the olefin, both of which are larger than a methyl group, the alkyl substituent that is cis to the intranucleophilic group participates more readily in β-hydride elimination. When one of the two alkyl substituents on the outer carbon atom of the olefin is a methyl group, β-hydride elimination proceeds selectively at the methylene side, thus both diastereomers can be prepared via switching the configuration of the olefin. Furthermore, the product can be converted to a pharmaceutical compound in high yields over three steps.