Enzymes typically exert tight control over the course of a reaction by embedding the transition states and intermediates in a precisely tailored binding pocket that allows no other than the desired orientation of the reactive groups. However, in a few notable cases, reactions in nature are (partially) uncatalyzed (33). For example, in certain cationic cyclizations of terpenes, the role of cyclases has been argued to be limited to generation and protection of the cationic intermediates without full control of the cyclization process (34). Given the mixture of products that result from CrISY and AmISY under in vitro reaction conditions, the cyclization half-reaction of iridoid synthase may be another such example of an uncatalyzed reaction. We hypothesize that the high selectivity of the reduction step and the relatively poor selectivity of the cyclization step in iridoid synthases are mechanistically best explained by enzymatic, stereoselective reduction followed by cyclization in an achiral environment outside the active site.