Stretchable chiral pockets for palladium-catalyzed highly chemo- and enantioselective allenylation

Yuchen Zhang,Shengming Ma,Xue Zhang

doi:10.1038/s41467-021-22498-1

Abstract

Pyrazolones are a vital class of heterocycles possessing various biological properties and much attention is paid to the diversified synthesis of enantiopure pyrazolone derivatives. We describe here the development of diphenylphosphinoalkanoic acid based chiral bisphosphine ligands, which are successfully applied to the palladium-catalyzed asymmetric allenylation of racemic pyrazol-5-ones. The reaction affords C-allenylation products, optically active pyrazol-5-ones bearing an allene unit, in high chemo- and enantioselectivity, with DACH-ZYC-Phos-C1 as the best ligand. The synthetic potential of the C-allenylation products is demonstrated. Furthermore, the enantioselectivity observed with DACH-ZYC-Phos-C1 is rationalized by density functional theory studies.

Highlights

Pyrazolones are a vital class of heterocycles possessing various biological properties[1]
Of particular interest are the pyrazolone derivatives with a chiral center (Fig. 1a): compound A and its derivatives were proven to be orally active growth hormone secretagogues[2,3]; compound B was used as a modulator of TRPM8;4 compound C shows remarkable anti-tumor activity related to lung, colon, and breast cancer cell[5,6]
Much attention has been paid to the diversified synthesis of bioactive enantiopure pyrazolone derivatives[7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]

Summary

Introduction

Pyrazolones are a vital class of heterocycles possessing various biological properties and much attention is paid to the diversified synthesis of enantiopure pyrazolone derivatives. Further optiminization was performed: the reactions at 60 °C and 80 °C afforded (S)-3aa in 75 and 80% yields, respectively, with a similar ee together with 4% of the N-allenylation product 4aa (Table 1, entries 2 and 3).

Results

Conclusion