Abstract Light-induced 2 + 2 cycloaddition is the most straightforward way to generate cyclobutanes, which are core structures of many natural products, drugs and bioactive compounds. Despite continuous advances in selective 2 + 2 cycloaddition research, general method for intermolecular photocatalysis of acyclic olefins with specific regio- and diastereoselectivity, for example, syn -head-to-head ( syn -HH) cyclobutane derivatives, is still lack of development but highly desired. Herein, we report a cage-confined photocatalytic protocol to enable unusual intermolecular 2 + 2 cycloaddition for α,β -unsaturated carbonyl compounds. The syn -HH diastereomers are readily generated with diastereoselectivity up to 99%. The cage-catalyst is highly efficient and robust, covering a diverse substrate range with excellent substituent tolerance. The mimic-enzyme catalysis is proposed through a host-guest mediated procedure expedited by aqueous phase transition of reactant and product, where the supramolecular cage effect plays an important role to facilitate substrates inclusion and pre-orientation, offering a promising avenue for general and eco-friendly cycloaddition photocatalysis with special diastereoselectivity.