Dedicated to Professor Ronald Breslow on the occasion of his 82nd birthdayPlants of the Euphorbiaceae family are sources of several important collections of secondary metabolites, one being the securinega alkaloids (1-5 [2] and 7, Scheme 1). [1] These materials possess unique frameworks typically characterized by a bridged, tetracyclic substructure bearing a strained a,b,g,dunsaturated lactone motif (as in 1-5), though rearranged variants of such domains (such as in 7) [3] also exist. They also display intriguing biological activity; [4] for instance, securinine (1), the most abundant member of the family, is a potent GABA antagonist. Given these attributes, it is unsurprising that the synthetic community has devoted significant attention to this collection of compounds, [5] particularly to the challenges posed by the key shared domains within 1-5. Indeed, since the inaugural total synthesis of securinine (1) by Horii in 1966, [5a] several other successful and highly creative approaches for forging their fused bicyclic butenolide domains have been disclosed, efforts that include selenoxide eliminations, [5b,e,f,h,i,r] intramolecular Wittig olefinations, [5e,f,o,p,t-v] ring-closing metatheses, [5j-p,s,x] and alkylation of allylic bromides or mesylates. [5a,h,i-m,q,t-v,x] However, most of these strategies require multiple steps to execute, typically constituting the longest (and least efficient) portion of the overall route. Here, we disclose a new disconnection for this critical domain, one that uses a simple, acyclic starting material and a novel N-heterocyclic carbene (NHC)-catalyzed reaction [6,7] to forge the entire butenolide system in a single step. We highlight its utility through a concise and efficient synthesis of 3-deshydroxy-secuamamine A (6, an analog of 5 [2] and a structural isomer of 1) as well as the core framework of 1-3, and indicate preliminary results of the components necessary for its successful application in other contexts.Our generalized approach to quickly fashion the butenolide domains of the securinega class is shown in the lower half of Scheme 1, using target 6 for purposes of illustration. As indicated, we envisioned that this entire key motif could be accessed from an appropriate linear enynal precursor (8) through an intramolecular NHC-catalyzed homoenolate addition onto the lone ketone followed by lactonization.
