Research Interests

 

Development of new organic synthetic methodology, asymmetric synthesis, total synthesis of natural products, and studies on the target identification, therapeutic applications and medicinal chemistry of natural products.

 

New Synthetic Methodology
 
Copper Hydride-Mediated Reactions

Copper is the least expensive of the coinage metals, and comparatively non-toxic. Reactions mediated or catalyzed by copper can be highly practical for industry. We have been working on various transformations mediated by ligated copper hydrides.

Representative publications:

  • Tandem Conjugate Reduction-Aldol Cyclizations Using Stryker's Reagent. Chiu, P.* Szeto, C. P.; Geng, Z.; Cheng, K. F. Org. Lett. 2001, 3, 1901–1903. 

  • Reductive and Catalytic Reductive Aldol Cyclizations of Alkynediones Induced by Stryker’s Reagent. Chiu, P.*; Leung, S. K. Chem. Commun. 2004, 2308–2309. 

  • Reductive Intramolecular Henry Reactions Induced by Stryker’s Reagent. Chiu, P.*; Chung, W. K. Synlett, 2005, 55–58.

  • Copper-Catalyzed Hydrostannation of Activated Alkynes. Leung, L. T.; Leung, S. K.; Chiu, P.* Org. Lett. 2005, 7, 5249–5252.

  • Desymmetrizing Reductive Aldol Cyclizations of Enethioate Derivatives of 1,3-Diones Catalyzed by Chiral Copper Hydride. Ou, J.; Wong, W. T.; Chiu, P.* Org. Biomol. Chem. 2012, 10, 5971–5978.

  • Copper Hydride-Catalyzed Reductive Claisen Rearrangements. Wong, K. C.; Ng, E.; Wong, W. T.; Chiu, P.* Chem. – Eur. J. 2016, 22, 3709–3712. 

Carbenes for Synthesis 

Metal carbenes are reactive and versatile intermediates for organic synthesis. We have been using them in cyclizations to generate ylide intermediates which can in turn undergo domino cycloadditions to form complex polycyclic frameworks. We have also studied the metal-catalyzed reaction of alpha-diazo-beta-hydroxydiazoketones which rearrange to form a series of [m.n.1] bicyclic scaffolds. We are studying these reactions to exploit them for the synthesis of natural products.

Representative publications:

  • A Rhodium Carbene Cyclization-Cycloaddition Cascade Strategy toward the Pseudolaric Acids. Chiu, P.*; Chen, B.; Cheng, K. F. Org. Lett. 2001, 3, 1721–1724. 

  • Allenes as dipolarophiles in the intramolecular carbene cyclization cycloaddition cascade reaction. Zhang, X.; Ko, R. Y. Y.; Li, S.; Miao, R.; Chiu, P.* Synlett, 2006, 1197–1200.

  • The Rhodium-Catalyzed Carbene Cyclization Cycloaddition Cascade Reaction of Vinylsulfonates. Shi, B.; Merten, S., Wong, D. K. Y.; Chu, J. C. K.; Liu, L. L.; Lam, S. K.; Jäger, A.; Wong, W. T.; Chiu, P.*; Metz, P.* Adv. Synth. Catal. 2009, 351, 3128–3132.

  • Rearrangements of a-Diazo-b-hydroxyketones ones for the synthesis of bicyclo[m.n.1]alkanones. Li, Z.; Lam, S. M.; Ip, I.; Wong, W. T.; Chiu, P.* Org. Lett. 2017,  http://dx.doi.org/10.1021/acs.orglett.7b01963

Cycloadditions for Synthesis

Representative publications:

  • Inter- and intramolecular [4+3] cycloadditions using epoxy enol silanes as functionalized oxyallyl cation precursors. Chung, W. K.; Lam, S. K.; Lo, B.; Liu, L. L.; Wong, W. T., Chiu, P.* J. Am. Chem. Soc. 2009, 131, 4556–4557.

  • Facial Selectivity and Regiospecificity in the (4+3) Cycloaddition of Epoxy Enol Silanes. Lo, B.; Chiu, P.* Org. Lett. 2011, 13, 864–867. 

  • Asymmetric (4+3) Cycloadditions Of Optically Enriched Epoxy Enolsilanes. Lo, B.; Lam, S.; Wong, W. T.; Chiu, P.* Angew. Chem., Int. Ed. 2012, 51, 12120–12123.

  • Intermolecular (4+3) Cycloadditions of Aziridinyl Enolsilanes. Lam, S. K.; Lam, S.; Chiu, P.* Chem. Commun. 2014, 50, 1738–1741.

  • Concerted Ring-Opening and Cycloaddition of Chiral Epoxy Enolsilanes with Dienes. Krenske, E. H.*; Lam, S.; Ng, J. P. L.; Lo, B.; Lam, S. K.; Chiu, P.*; Houk, K. N.* Angew. Chem., Int. Ed. 2015, 54, 7422–7425.

  • Dearomative Intramolecular (4+3) Cycloadditions of Arenes with Epoxy and Aziridinyl Enolsilanes. Ling, J.; Lam, S.; Low, K.-H.; Chiu, P.* Angew. Chem., Int. Ed. 2017, 56, 8879–8882.

We are developing novel reactions for the synthesis of cycloheptanoids, for which there are fewer methods to synthesize in an enantioselective fashion with multiple stereocentres and functional groups. We have been examining (4+3) cycloadditions and (5+2) cycloadditions for this purpose.

Total Synthesis of
Natural Products and Bioactive Compounds
 

We have an ongoing program in the synthesis of architecturally and biologically interesting compounds. “Total synthesis” is the research to design and execute a series of reactions to construct complex, naturally occurring molecules. In this field, the target is precise and non-negotiable. It is this demand that challenges the imagination of synthetic chemists and inspires the drive to develop better reactions. The pharmaceutical industry considers this the best training for graduate students to become medicinal chemists.  Many organic chemists view total synthesis as the “Mount Everest” for strategy design and for demonstrating the utility and scope of reactions.  

Representative publications:

  • Total synthesis of Pseudolaric Acid A. Geng, Z.; Chen, B.; Chiu, P.* Angew. Chem., Int. Ed. 2006, 45, 6197–6201.

  • Total Synthesis of (–)-Indicol. Lam, S. K.; Chiu, P.* Chem. – Eur. J. 2007, 13, 9589–9599.

  • Total Synthesis of (–)-Dolastatrienol.  Leung, L. T.; Chiu, P.* Chem. – Asian J. 2015, 10, 1042–1049. 

  • Formal Total Synthesis of (+)-Cortistatin A and J. Kuang, L.; Liu, L. L.; Chiu, P. Chem. – Eur. J. 2015, 21, 14287–14291.

  • An approach to the welwistatin core via a diazoketone rearrangement-ring expansion strategy.  Lam. S. M.; Wong, W. T.; Chiu, P.* Org. Lett. 2017, 19, 0000.  http://dx.doi.org/10.1021/acs.orglett.7b01988

 

Target Identification and Medicinal Chemistry of Bioactive Natural Products 
 

In collaboration with computational chemists and biologists, we have applied synthesis to identify the biological targets and mechanisms of action of bioactive natural products.  We have also applied synthesis to optimize molecular drug leads.

 

Representative publications:

  • Pseudolaric acid B, a novel class of microtubule-destabilizing agent circumvents a multi-drug resistant phenotype and exhibits antitumor activity in vivo. Wong, V. K. M.; Chiu, P.; Chung, S. S. M.; Chow, L. M. C.; Zhao, Y. Z.; Yang, B. B.; Ko, B. C. B.* Clin. Cancer Res. 2005, 11, 6002–6011.

  • Alisol B, a novel inhibitor of the SERCA pump, induces autophagy, ER-stress and apoptosis. Law, B. Y. K.; Wang, M.; Ma, D.-L.; Al-Mousa, F.; Michelangeli, F.; Cheng, S.-H..; Ng, M. H. L.; To, K.-F.; Mok, A. Y. F.; Ko, R. Y. Y.; Lam, S. K.; Chen, F.; Che, C.-M.; Chiu, P.*; Ko, B. C. B.*  Mol. Cancer Ther. 2010, 69, 718–730.

  • Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library. Ma, D. L.;* Chan, D. S.-H.; Wei, G.; Zhong, H. J.; Yang, H.; Leung, L. T.; Gullen, E. A.; Chiu, P.;* Cheng, Y. C.;* Leung, C. H.* Chem. Commun. 2014, 13885–13888.

  • Tetrandrine, an activator of autophagy, induces autophagic cell death via PKC-α inhibition and mTOR-dependent mechanisms. Wong, V. K. W.; Zeng, W.; Chen J.; Yao, X. J.; Leung, E. L.; Wang Q. Q.; Chiu, P.*; Ko, B. C. B.*; Law, B. Y. K.* Front. Pharmacol. 2017, 8: 351.

  • A Natural Product-like JAK2/STAT3 Inhibitor Induces Apoptosis of Malignant Melanoma Cells. Wu, K. J.; Huang J. M.; Zhong, H. J.; Dong Z. Z.; Liu, C.; Lu, J.-J.; Chen, X. P.;  Chiu, P; Kwong, D. W.; Han, Q. B.; Ma, D. L.*, Leung, C. H.* PLoS One, 2017, 12(6) e0177123.

Department of Chemistry

Faculty of Science

The University of Hong Kong

© 2020 by Pauline Chiu