An Organocatalytic Asymmetric Nazarov Cyclization

An organocatalytic asymmetric Nazarov cyclization of diketoesters has been developed that proceeds by means of a dual activation mechanism. Screening of a number of catalysts led to a new thiourea that incorporates a primary amino group. The method gives rise to cyclic products with two adjacent quaternary asymmetric carbon atoms, one of which is an all carbon atom stereocenter, with complete or nearly complete diastereoselectivity, and in high or very high enantiomeric excess. A brief and very convenient synthesis of the acyclic diketoester starting materials through nucleophilic addition to a ketene has been described. In earlier work we have described cyclizations of α-ketoenones under a variety of mild reaction conditions. For example, ketoenone 1 can be converted to α-hydroxycyclopentenone 2 in 71 % yield by exposure to silica gel and triethylamine in the absence of solvent at room temperature (eq 1).1 Alternatively, treatment of 1 with lithium tetramethylpiperidide or with Yb(OTf)3 and pyrrolidine leads to 2 in 71 % and 63 % yield, respectively.2 There are earlier examples of diketone cyclizations that lead to α-hydroxycyclopentenones that may may proceed through a similar mechanism. For example, in 1975 Weinreb and Auerbach, inspired by an observation published in 1965 by Muxfeldt and coworkers,3 described the cyclization of diketone 3 to 4 under the influence of Mg(OMe)2 during their synthesis of cephalotaxine (eq 2).4,5 Both Muxfeldt and [1