Diastereoselective double Heck cyclizations of cyclohexene diamides >1 and >3 form contiguous quaternary stereocenters, with diastereoselection being controlled by the trans diol-protecting group. In this, the first in a series of two papers, the origin of diastereoselection in the first ring closure step of these reactions is examined. Nine simplified analogues of >1 and >3 were synthesized and cyclized to discern what structural features are required to realize high diastereoselection in the first intramolecular Heck reaction. These studies show that high stereoselection (>20:1) does not arise from a single structural feature: it is seen only in substrates that contain both a trans acetonide and a tertiary amide substituent at C2. Two subtle factors appear to be involved: (1) Avoidance of eclipsing interactions between the forming C–C bond and the pseudoaxial hydrogen atom at C6, and between the pseudoequatorial hydrogen atom at C6 and the carbonyl carbon of the forming spirooxindole; (2) The vinylic amide substituent that is not involved in the insertion event, preferentially adopts a perpendicular conformation placing the sterically bulky NR2 over the alkene π-bond. Syn-pentane-like interactions between this substituent and C3 of the cyclohexene are avoided in the favored insertion topography. These two effects, when combined, produce a highly diastereoselective process.
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