Advancing the science of molecular synthesis

8 Sep 2016. NUS chemists have developed a new method of using phosphine catalysts to produce organic compounds with high stereoselectivity.

From designing functional materials to preparing bioactive drugs, organic synthesis plays an indispensable role in improving our lives. Organic synthesis involves the development of various types of molecular compounds from basic building blocks. Through the use of synthetic development methods, organic chemists working in this area design and create new molecules, resulting in molecules with better functionalities and higher yields.

Prof LU Yixin and his research team from the Department of Chemistry at NUS have developed a facile and efficient phosphine-catalysed method to produce 3,2’-pyrrolidinyl spirooxindoles, a molecular compound with high medicinal potential using ketimines. Molecular structures with nitrogen-containing ring systems are widely found in natural products and are very valuable as synthetic intermediates in the development of other products. Chemical reactions in which phosphine is used as a catalyst are one of the best methods for obtaining these structures and have been widely employed in the synthesis of many natural products and bioactive molecules. However, ketimines, a chemical compound, is seldom used in such reactions. This is likely to be due to its low reactivity with other compounds and difficulty in getting high yields. The research team discovered that the amino acid-derived chiral phosphine (see molecule structure 4a) developed by them can initiate the cyclisation reaction between unreactive ketimines and allenoates to obtain nearly perfect enantioselective spiro-products giving excellent yield, in one single step, and within a very short period of time.

This synthetic method may lead to a new and salient way to produce valuable precursors of, for instance, a HIV-1 inhibitor (blue), a cholinesterase inhibitor (green), and an antibacterial agent (red) with the spirocyclic frameworks.

Figure shows the chemical synthesis which can be triggered by the phosphine molecule 4a.

Reference

Han X., Chan W.-L., Yao W., Wang Y., Lu Y. “Phosphine-mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates”. Angew. Chem. Int. Ed. (2016), 55, 6492.