Palladium-Catalysed Decarboxylative Asymmetric Allylic Alkylation for the Synthesis of Chiral Four-Membered Ring-Containing Spirocycles

Spirocycles were first synthesised in the late 1890s and can be described as chemical structures which consist of two perpendicular rings linked together by one common atom. In particular, incorporation of strained four-membered rings into spirocyclic fragments of drug compounds is of great interest due to their rigid structure. This reduces conformational flexibility which could improve binding at the target receptor. It is, therefore, not surprising that there has been a significant increase in journal and patent references over the past 15 years of spirocycles containing at least one four-membered ring.1 Spirocycles, are present in many biologically active natural products and drug molecules and possess many structural advantages over the corresponding conventional saturated heterocyclic analogues; such as lower lipophilicity, increased aqueous solubility as well as improved metabolic stability.2

Decarboxylative asymmetric allylic alkylation (DAAA) is a catalytic reaction which can be used for the construction of enantiopure, quaternary carbon atoms and has been very successful for a broad range of substrates to generate asymmetric C-C, C-N and C-O bonds.3
The aim of this project involves the development of the Pd-catalysed DAAA reaction of strained four-membered sulfones to generate enantiopure centres, and, upon further functionalisation and spirocyclisation, a series of novel enantiopure spirocycles for medicinal chemistry applications. This methodology will subsequently be extended to other four-membered substrates to provide spirocycles based on sultam, oxetane and azetidine rings.


1 E. M. Carreira and T. C. Fessard, Chem. Rev., 2014, 114, 8257-8322.
2 J. A. Burkhard, C. Gue'rot, H. Knust, M. Rogers-Evans and E. M. Carreira, Org. Lett., 2010, 12, 1944-1947.
3 D. C. Behenna and B. M. Stoltz, J. Am. Chem. Soc., 2004, 126, 15044-15045.