In May-17-2019, the Xu lab of School of Medicine and Pharmacy, Ocean University of China, reported “Highly Regio- and Enantio-Selective Dienylation of p-Quinone Methides Enabled by an Organocatalyzed Isomerization/Addition Cascade of Allenoates” online in ACS journal《Organic Letters》(Org. Lett., 2019, 21, 3963-3967.)
An important structural motifs-dienes and diaryl, especially functionalized ones, are widely existed in many natural products and pharmaceuticals. For examples, a candidate drug molecule CDP840 (inhibitor of PDE4), drug molecule R-tolterodine and chlorpheniramine. Moreover, they also serve as key building blocks in modern organic synthesis and material science due to its extensive application and transformation.
Recently, on the basis of previous work (Chem. Sci., 2015, 6, 7319; Chem-Eur. J., 2014, 20, 15325), they reporteda novel catalytic asymmetric dienylation of allenoates with para-quinone methides in the presence of chiral phosphine (R)-SITCP,affordingfunctionalizeddienyl with diarylmethine compounds in good yields (up to 91% yield) with excellent enantioselectivities (up to 98% ee) under mild condition. The wide substrate scope has been also examined (more than 30 examples). This is the first time realized allenoates isomerization to a chiral conjugated diene in asymmetric synthesis which expanded the view of allene chemistry. Besides, it provides a new way to form dienyl compounds. Deuterium labelling and control experiments reveal the plausible mechanism of this allenoate dienylation reaction.
Further work is ongoing aim at synthesis of active drug molecules by this methodology. Preliminary results showed that some compounds have strong cytotoxicity (MKN-45 IC50 up to 2.2 mM, for several other human cancer cells IC50 were between 2.2 to 7.2 mM), part of the biological activity tests were supported by Prof. Jin-Bo Yang and Prof. Xin Wang.
This work is supported by “1000 Talents Plan for Young Professionals” and OUC for a startup fund, NSFC (No. U1606403 & No.U1706213), the pilot QNLMST (No.2015ASTP-ES14 & No.2018SDKJ0403), and National Science and Technology Major Project of China (No. 2018ZX09735-004) for research grants. De Wang and Prof. Tao Xu are corresponding authors of this work, part of the work is finished by Z.-F. Song and W.-J. Wang from School of Medicine and pharmacy (OUC).
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